ORCID Profile
0000-0001-9447-2292
Current Organisation
University of Queensland
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Biologically Active Molecules | Gene Expression (incl. Microarray and other genome-wide approaches) | Biologically active molecules | Pollution and contamination | Natural products and bioactive compounds | Environmental biotechnology | Animal protection (incl. pests and pathogens) | Macromolecular and Materials Chemistry | Microbiology | Nanochemistry and Supramolecular Chemistry | Chemical Characterisation of Materials | Veterinary bacteriology | Biodiscovery | Pollution and contamination not elsewhere classified | Bacteriology
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences |
Publisher: Springer Science and Business Media LLC
Date: 19-01-2021
DOI: 10.1038/S42003-020-01530-Y
Abstract: Antimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections. Unfortunately, there are few new therapeutics in the clinical pipeline, particularly for Gram-negative bacteria. We now present a detailed evaluation of the antimicrobial activity of cannabidiol, the main non-psychoactive component of cannabis. We confirm previous reports of Gram-positive activity and expand the breadth of pathogens tested, including highly resistant Staphylococcus aureus , Streptococcus pneumoniae , and Clostridioides difficile . Our results demonstrate that cannabidiol has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy. Multiple mode-of-action studies point to membrane disruption as cannabidiol’s primary mechanism. More importantly, we now report for the first time that cannabidiol can selectively kill a subset of Gram-negative bacteria that includes the ‘urgent threat’ pathogen Neisseria gonorrhoeae . Structure-activity relationship studies demonstrate the potential to advance cannabidiol analogs as a much-needed new class of antibiotics.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0CC90250K
Abstract: Correction for ‘Chemical synthesis of human trefoil factor 1 (TFF1) and its homodimer provides novel insights into their mechanisms of action’ by Nayara Braga Emidio et al. , Chem. Commun. , 2020, DOI: 10.1039/D0CC02321C.
Publisher: Cold Spring Harbor Laboratory
Date: 08-05-2017
DOI: 10.1101/134684
Abstract: Extensively drug-resistant Klebsiella pneumoniae (XDR-KP) infections cause high mortality and are disseminating globally. Identifying the genetic basis underpinning resistance allows for rapid diagnosis and treatment. XDR isolates sourced from Greece and Brazil, including nineteen polymyxin-resistant and five polymyxin-susceptible strains, underwent whole genome sequencing. Approximately 90% of polymyxin resistance was enabled by alterations upstream or within mgrB . The most common mutation identified was an insertion at nucleotide position 75 in mgrB via an ISK pn26 -like element in the ST258 lineage and ISK pn13 in one ST11 isolate. Three strains acquired an IS1 element upstream of mgrB and another strain had an ISK pn25 insertion at 133 bp. Other isolates had truncations (C28STOP, Q30STOP) or a missense mutation (D31E) affecting mgrB . Complementation assays revealed all mgrB perturbations contributed to resistance. Missense mutations in phoQ (T281M, G385C) were also found to facilitate resistance. Several variants in phoPQ co-segregating with the ISKpn26-like insertion were identified as potential partial suppressor mutations. Three ST258 s les were found to contain subpopulations with different resistance conferring mutations, including the ISKpn26-like insertion colonising with a novel mutation in pmrB (P158R), both confirmed via complementation assays. We also characterized a new multi-drug resistant Klebsiella quasipneumoniae strain ST2401 which was susceptible to polymyxins. These findings highlight the broad spectrum of chromosomal modifications which can facilitate and regulate resistance against polymyxins in K. pneumoniae . Whole genome sequencing of the 24 clinical isolates has been deposited under BioProject PRJNA307517 ( ioproject/PRJNA307517 ). Klebsiella pneumoniae contributes to a high abundance of nosocomial infections and the rapid emergence of antimicrobial resistance hinders treatment. Polymyxins are predominantly utilized to treat multidrug-resistant infections, however, resistance to the polymyxins is arising. This increasing prevalence in polymyxin resistance is evident especially in Greece and Brazil. Identifying the genomic variations conferring resistance in clinical isolates from these regions assists with potentially detecting novel alterations and tracing the spread of particular strains. This study commonly found mutations in the gene mgrB , the negative regulator of PhoPQ, known to cause resistance in KP. In the remaining isolates, missense mutations in phoQ were accountable for resistance. Multiple novel mutations were detected to be segregating with mgrB perturbations. This was either due to a mixed heterogeneous s le of two polymyxin-resistant strains, or because of multiple mutations within the same strain. Of interest was the validation of novel mutations in phoPQ segregating with a previously known ISK pn26 -like element in disrupted mgrB isolates. Complementation of these phoPQ mutations revealed a reduction in minimum inhibitory concentrations and suggests the first evidence of partial suppressor mutations in KP. This research builds upon our current understanding of heteroresistance, lineage specific mutations and regulatory variations relating to polymyxin resistance.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0CB00118J
Abstract: Macrolide fluorescent probes illuminate the interactions between antibiotics and bacteria, providing new insight into mechanisms of resistance.
Publisher: Cold Spring Harbor Laboratory
Date: 29-11-2018
DOI: 10.1101/482661
Abstract: Klebsiella pneumoniae frequently harbour multidrug resistance and current methodologies are struggling to rapidly discern feasible antibiotics to treat these infections. While rapid DNA sequencing has been proposed for prediction of resistance profile the role of rapid RNA sequencing has yet to be fully explored. The MinION sequencer can sequence native DNA and RNA in real-time, providing an opportunity to contrast the utility of DNA and RNA for prediction of drug susceptibility. This study interrogated the genome and transcriptome of four extensively drug-resistant (XDR) K. pneumoniae clinical isolates. The majority of acquired resistance (≥75%) resided on plasmids including several megaplasmids (≥100 kbp). DNA sequencing identified most resistance genes (≥70%) within 2 hours of sequencing. Direct RNA sequencing (with a ∼6x slower pore translocation) was able to identify ≥35% of resistance genes, including aminoglycoside, β-lactam, trimethoprim and sulphonamide and also quinolone, rif icin, fosfomycin and phenicol in some isolates, within 10 hours of sequencing. Polymyxin-resistant isolates showed a heightened transcription of phoPQ ( ≥2-fold) and the pmrHFIJKLM operon (≥8-fold). Expression levels estimated from direct RNA sequencing displayed strong correlation (Pearson: 0.86) compared to qRT-PCR across 11 resistance genes. Overall, MinION sequencing rapidly detected the XDR K. pneumoniae resistome and direct RNA sequencing revealed differential expression of these genes.
Publisher: Microbiology Society
Date: 03-2018
Publisher: American Chemical Society (ACS)
Date: 06-2021
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2022
DOI: 10.1101/2022.04.05.487095
Abstract: Tuberculosis remains one of the leading causes of death from a single infectious agent, surpassing both AIDS and malaria. In recent years, two bicyclic nitroimidazole drugs, delamanid and pretomanid have been approved to treat this airborne infection. This has spurred a renewed interest in developing new and improved nitroimidazole analogs. We have previously identified a new bicyclic heteroaromatic subclass, the nitroimidazopyrazinones, with substituted analogs showing promising activity against Mycobacterium tuberculosis under both aerobic and hypoxic environments. A second generation of nitroimidazopyrazinones with extended biaryl side chain also possessed good antiparasitic activity against Trypanosoma brucei brucei and Trypanosoma cruzi , suggesting the utility of this new scaffold for development into potential candidates against both tuberculosis and the kinetoplastid parasites which cause neglected tropical diseases. In this study, we further evaluated the properties of nitroimidazopyrazinone derivatives by assessing their selectivity against different mycobacterial species, measuring their reduction potential, and determining the kinetic parameters as substrates of the deazaflavin-dependent nitroreductase (Ddn), which is the activating enzyme of delamanid and pretomanid in M. tuberculosis . We also conducted an in vivo evaluation of a lead compound, MCC8967 that demonstrated a favorable pharmacokinetic profile, with good oral bioavailability and efficacy in an acute M. tuberculosis infection model. Two other promising compounds MCC9481 and MCC9482, with good in vitro activity (IC 50 = 0.016 and 0.10 µM, respectively) against T. cruzi , the causative agent for Chagas diseases, were similarly tested for in vivo activity. These compounds also exhibited good oral bioavailability, and transiently reduced the acute-stage parasite burden by ‒99% at doses of 50 mg/kg once or twice daily, similar to benznidazole at 100 mg/kg once daily. Overall, we have demonstrated that active nitroimidazopyrazinones have potential to be developed as clinical candidates against both tuberculosis and Chagas disease. Tuberculosis and parasitic infections continue to impose a significant threat to public health and economic growth worldwide. Most of the efforts to control these diseases still rely on drug treatments with limited effectiveness and significant side effects. There is now an urgent need to develop new treatments to combat these infections. Here, we report the in vitro and in vivo profile of a new bicyclic nitroimidazole subclass, namely nitroimidazopyrazinones, against mycobacteria and Trypanosoma cruzi . We found that derivatives with monocyclic side chains are selective against Mycobacterium tuberculosis , the causative agent of tuberculosis, but not active against other nontuberculosis mycobacteria. In an acute mouse model, they were able to reduce the bacterial load in lungs via oral administration. From a biochemistry perspective, we demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in M. tuberculosis . We also showed that derivatives with extended biaryl side chain were effective in suppressing infection in an acute T. cruzi infected murine model, with satisfactory oral bioavailability. These findings improve the understanding of the biological profile of nitroimidazopyrazinones for further development as potential antitubercular and antiparasitic agents.
Publisher: Wiley
Date: 05-09-2023
Abstract: Infections associated with antimicrobial resistance (AMR) are poised to become the leading cause of death in the next few decades, a scenario that can be ascribed to two phenomena: antibiotic over‐prescription and a lack of antibiotic drug development. The crowd‐sourced initiative CO‐ADD has been testing research compounds contributed by researchers around the world to find new antimicrobials to combat AMR, and during this c aign has found that metallodrugs might be a promising, yet untapped source. To this end, we submitted 18 Pd(II) and Ru(II) – pyridyl‐1,2,3‐triazolyl complexes which were developed as catalysts for their antimicrobial properties. It was found that the Pd‐complexes possessed potent antifungal activity, especially Pd1, with MICs between 0.06 – 0.125 µg/mL against C. glabrata. The in vitro studies were extended to in vivo studies in G. mellonella larvae where it was established that the compounds were non‐toxic. Here we effectively demonstrate the potential of Pd(II)‐pyta complexes as antifungal agents.
Publisher: American Society for Microbiology
Date: 2019
DOI: 10.1128/AAC.01760-18
Abstract: The determination of antibiotic potency against bacterial strains by assessment of their minimum inhibitory concentration normally uses a standardized broth microdilution assay procedure developed more than 50 years ago. However, certain antibiotics require modified assay conditions in order to observe optimal activity.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.TIM.2018.10.007
Abstract: The Eagle effect describes a phenomenon in which bacteria or fungi exposed to concentrations of antibiotic higher than an optimal bactericidal concentration (OBC) have paradoxically improved levels of survival than at the OBC due to a decreased net rate of cell death. Despite extensive observational reports of this effect in different microorganisms, its underlying mode of action is not well understood. Although aspects of the Eagle effect resemble persistence, there is strong evidence that these phenomena are substantially different phenotypic responses to antibiotic treatment. We present an overview of the microorganism and antimicrobial combinations in which the Eagle effect has been observed. Proposed underlying mechanism(s) are assessed, and the Eagle effect and microbial persistence are compared and contrasted. The clinical relevance of the Eagle effect is reviewed, incorporating evidence from experimental in vitro and in vivo studies, as well as clinical reports.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.TIBTECH.2018.01.004
Abstract: Better understanding how multidrug-resistant (MDR) bacteria can evade current and novel antibiotics requires a better understanding of the chemical biology of antibiotic action. This necessitates using new tools and techniques to advance our knowledge of bacterial responses to antibiotics, ideally in live cells in real time, to selectively investigate bacterial growth, ision, metabolism, and resistance in response to antibiotic challenge. In this review, we discuss the preparation and biological evaluation of fluorescent antibiotics, focussing on how these reporters and assay methods can help elucidate resistance mechanisms. We also examine the potential utility of such probes for real-time in vivo diagnosis of infections.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2023
DOI: 10.1038/S42003-023-04745-X
Abstract: Antimicrobial resistance is an urgent threat to human health, and new antibacterial drugs are desperately needed, as are research tools to aid in their discovery and development. Vancomycin is a glycopeptide antibiotic that is widely used for the treatment of Gram-positive infections, such as life-threatening systemic diseases caused by methicillin-resistant Staphylococcus aureus (MRSA). Here we demonstrate that modification of vancomycin by introduction of an azide substituent provides a versatile intermediate that can undergo copper-catalysed azide−alkyne cycloaddition (CuAAC) reaction with various alkynes to readily prepare vancomycin fluorescent probes. We describe the facile synthesis of three probes that retain similar antibacterial profiles to the parent vancomycin antibiotic. We demonstrate the versatility of these probes for the detection and visualisation of Gram-positive bacteria by a range of methods, including plate reader quantification, flow cytometry analysis, high-resolution microscopy imaging, and single cell microfluidics analysis. In parallel, we demonstrate their utility in measuring outer-membrane permeabilisation of Gram-negative bacteria. The probes are useful tools that may facilitate detection of infections and development of new antibiotics.
Publisher: MDPI AG
Date: 03-04-2022
DOI: 10.3390/PHARMACEUTICS14040786
Abstract: Polymyxins have resurged as the last-resort antibiotics against multidrug-resistant Acinetobacter baumannii. As reports of polymyxin resistance in A. baumannii with monotherapy have become increasingly common, combination therapy is usually the only remaining treatment option. A novel and effective strategy is to combine polymyxins with non-antibiotic drugs. This study aimed to investigate, using untargeted metabolomics, the mechanisms of antibacterial killing synergy of the combination of polymyxin B with a synthetic cannabidiol against A. baumannii ATCC 19606. The antibacterial synergy of the combination against a panel of Gram-negative pathogens (Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa) was also explored using checkerboard and static time-kill assays. The polymyxin B–cannabidiol combination showed synergistic antibacterial activity in checkerboard and static time-kill assays against both polymyxin-susceptible and polymyxin-resistant isolates. The metabolomics study at 1 h demonstrated that polymyxin B monotherapy and the combination (to the greatest extent) significantly perturbed the complex interrelated metabolic pathways involved in the bacterial cell envelope biogenesis (amino sugar and nucleotide sugar metabolism, peptidoglycan, and lipopolysaccharide (LPS) biosynthesis), nucleotides (purine and pyrimidine metabolism) and peptide metabolism notably, these pathways are key regulators of bacterial DNA and RNA biosynthesis. Intriguingly, the combination caused a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids) compared to very minimal changes induced by monotherapies. At 4 h, polymyxin B–cannabidiol induced more pronounced effects on the abovementioned pathways compared to the minimal impact of monotherapies. This metabolomics study for the first time showed that in disorganization of the bacterial envelope formation, the DNA and RNA biosynthetic pathways were the most likely molecular mechanisms for the synergy of the combination. The study suggests the possibility of cannabidiol repositioning, in combination with polymyxins, for treatment of MDR polymyxin-resistant Gram-negative infections.
Publisher: SPIE
Date: 07-03-2019
DOI: 10.1117/12.2507329
Publisher: American Chemical Society (ACS)
Date: 30-09-2016
DOI: 10.1021/ACS.JMEDCHEM.6B00319
Abstract: Unusual amino acids are fundamental building blocks of modern medicinal chemistry. The combination of readily functionalized amine and carboxyl groups attached to a chiral central core along with one or two potentially erse side chains provides a unique three-dimensional structure with a high degree of functionality. This makes them invaluable as starting materials for syntheses of complex molecules, highly erse elements for SAR c aigns, integral components of peptidomimetic drugs, and potential drugs on their own. This Perspective highlights the ersity of unnatural amino acid structures found in hit-to-lead and lead optimization c aigns and clinical stage and approved drugs, reflecting their increasingly important role in medicinal chemistry.
Publisher: Wiley
Date: 30-01-2020
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.BMC.2016.03.053
Abstract: The spread of drug-resistant bacteria has imparted a sense of urgency in the search for new antibiotics. In an effort to develop a new generation of antibacterial agents, we have designed de novo charged lipopeptides inspired by natural antimicrobial peptides. These short lipopeptides are composed of cationic lysine and hydrophobic lipoamino acids that replicate the hiphilic properties of natural antimicrobial peptides. The resultant lipopeptides were found to self-assemble into nanoparticles. Some were effective against a variety of Gram-positive bacteria, including strains resistant to methicillin, daptomycin and/or vancomycin. The lipopeptides were not toxic to human kidney and liver cell lines and were highly resistant to tryptic degradation. Transmission electron microscopy analysis of bacteria cells treated with lipopeptide showed membrane-damage and lysis with extrusion of cytosolic contents. With such properties in mind, these lipopeptides have the potential to be developed as new antibacterial agents against drug-resistant Gram-positive bacteria.
Publisher: Wiley
Date: 30-01-2020
Abstract: New antibiotics and innovative approaches to kill drug‐resistant bacteria are urgently needed. Metal complexes offer access to alternative modes of action but have only sparingly been investigated in antibacterial drug discovery. We have developed a light‐activated rhenium complex with activity against drug‐resistant S. aureus and E. coli . The activity profile against mutant strains combined with assessments of cellular uptake and synergy suggest two distinct modes of action.
Publisher: Elsevier BV
Date: 09-2016
Publisher: American Chemical Society (ACS)
Date: 15-10-2019
DOI: 10.26434/CHEMRXIV.9956744.V1
Abstract: There is a dire need for new classes of antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Antibiotic compounds are notorious for not having very “drug-like” chemical structures. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). This work reveals the vast ersity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
Publisher: American Chemical Society (ACS)
Date: 16-08-2016
Publisher: American Chemical Society (ACS)
Date: 22-10-2019
DOI: 10.26434/CHEMRXIV.9956744.V2
Abstract: There is a dire need for new classes of antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Antibiotic compounds are notorious for not having very “drug-like” chemical structures. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). This work reveals the vast ersity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
Publisher: Future Science Ltd
Date: 06-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0CC02321C
Abstract: Chemical synthesis of gut peptide TFF1 and its homodimer was achieved by a two-fragment ligation strategy followed by oxidative folding.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JINORGBIO.2016.11.028
Abstract: Alternative solutions need to be developed to overcome the growing problem of multi-drug resistant bacteria. This study explored the possibility of creating complexes of antibiotics with metal ions, thereby increasing their activity. Analytical techniques such as isothermal titration calorimetry and nuclear magnetic resonance were used to examine the structure and interactions between Cu(II), Ag(I) or Zn(II) and β-lactam antibiotics. The metal-β-lactam complexes were also tested for antimicrobial activity, by micro-broth dilution and disk diffusion methods, showing a synergistic increase in the activity of the drugs, and enzymatic inhibition assays confirming inhibition of β-lactamases responsible for resistance. The metal-antibiotic complex concept was proven to be successful with the activity of the drugs enhanced against β-lactamase-producing bacteria. The highest synergistic effects were observed for complexes formed with Ag(I).
Publisher: Springer Science and Business Media LLC
Date: 29-06-2017
DOI: 10.1038/JA.2016.72
Abstract: There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.
Publisher: Informa UK Limited
Date: 10-11-2014
DOI: 10.1517/17425255.2014.967681
Abstract: Drug-induced nephrotoxicity contributes to the failure rate of investigational drugs during clinical trials. We are still not able to accurately predict drug-induced nephrotoxicity during early drug discovery and development. There is an urgent need for a robust screening system that can identify nephrotoxic compounds before they reach the clinic. This review discusses traditional and emerging kidney injury biomarkers that are used for the determination of nephrotoxicity and for evaluation and diagnosis of other kidney diseases. The potential for in vivo biomarkers to predict renal toxicity in high-throughput in vitro screening assays is discussed. We also compare cell types and highlight novel three-dimensional (3D) culture technologies with potential for in vitro prediction of nephrotoxicity. Traditional cell culture methods and cytotoxicity assays are well established as in vitro tests for nephrotoxicity but the correlation with in vivo results is extremely poor. Recently validated renal biomarkers show promise for early in vivo detection of nephrotoxicity, but have yet to be successfully applied for in vitro prediction of drug-induced nephrotoxicity. Advanced culture technologies 'kidney-on-a-chip' and 3D culture can produce biomarker signatures from relevant kidney cell types that show promise as better predictive systems.
Publisher: Springer Science and Business Media LLC
Date: 02-01-2018
DOI: 10.1038/S41467-017-02123-W
Abstract: The public health threat posed by a looming ‘post-antibiotic’ era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature’s control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N -terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the ‘vancapticins’, possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to ‘revitalise’ antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors.
Publisher: Future Science Ltd
Date: 05-2017
Abstract: The Community for Open Antimicrobial Drug Discovery (CO-ADD) is a not-for-profit, collaborative approach to discovering new antibiotics. We access novel chemical ersity from academic synthetic chemists, who collectively possess millions of untested compounds with chemical ersity that lie outside commercial collections. We perform high-throughput antimicrobial screening of pure compounds derived from both synthetic and natural sources free of charge. The resulting data can be used by participants for publication, patenting and development purposes, and is fed back into the research community through an open-access database after a 2-year period during which information is kept confidential to the provider. CO-ADD is fundamentally asking two questions: can the community work together to address the global threat of antimicrobial resistance and are there as yet undiscovered, novel antimicrobial compounds already present within our erse global chemistry community?
Publisher: Wiley
Date: 17-05-2016
DOI: 10.1038/ICB.2016.43
Abstract: The complement cascade is comprised of a highly sophisticated network of innate immune proteins that are activated in response to invading pathogens or tissue injury. The complement activation peptide, C5a, binds two seven transmembrane receptors, namely the C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2, or C5L2). C5aR2 is a non-G-protein-signalling receptor whose biological role remains controversial. Some of this controversy arises owing to the lack of selective ligands for C5aR2. In this study, a library of 61 peptides based on the C-terminus of C5a was assayed for the ability to selectively modulate C5aR2 function. Two ligands (P32 and P59) were identified as functionally selective C5aR2 ligands, exhibiting selective recruitment of β-arrestin 2 via C5aR2, partial inhibition of C5a-induced ERK1/2 activation and lipopolysaccharide-stimulated interleukin-6 release from human monocyte-derived macrophages. Importantly, neither ligand could induce ERK1/2 activation or inhibit C5a-induced ERK1/2 activation via C5aR1 directly. Finally, P32 inhibited C5a-mediated neutrophil mobilisation in wild-type, but not C5aR2(-/-) mice. These functionally selective ligands for C5aR2 are novel tools that can selectively modulate C5a activity in vitro and in vivo, and thus will be valuable tools to interrogate C5aR2 function.
Publisher: Elsevier BV
Date: 02-2020
Publisher: Springer Science and Business Media LLC
Date: 07-10-2015
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.MIB.2016.05.011
Abstract: The discovery of new antibiotics is crucial if we are to avoid a future in which simple infections once again lead to death. New antibiotics were traditionally discovered by analyzing extracts from cultured soil-derived microbes. However, in the last few years only a few new antibiotic classes have been identified using this method. Attempts to apply target-based screening approaches to antibiotic discovery have also proven to be unproductive. In this article, we describe how DNA sequencing and bioinformatic techniques are revolutionizing natural product discovery leading to new natural product antibiotics sourced from both cultivated and uncultivated microbes. New chemical structures are also being 'crowd sourced' from chemists around the world, and 'forgotten' antibiotics repositioned for clinical trials after chemical or biochemical modification of the original natural product. Collectively such approaches have the potential to rev antibiotic lead discovery and re-invigorate the antibiotic pipeline.
Publisher: Public Library of Science (PLoS)
Date: 23-12-2021
DOI: 10.1371/JOURNAL.PGEN.1009586
Abstract: The cell envelope is essential for viability in all domains of life. It retains enzymes and substrates within a confined space while providing a protective barrier to the external environment. Destabilising the envelope of bacterial pathogens is a common strategy employed by antimicrobial treatment. However, even in one of the best studied organisms, Escherichia coli , there remain gaps in our understanding of how the synthesis of the successive layers of the cell envelope are coordinated during growth and cell ision. Here, we used a whole-genome phenotypic screen to identify mutants with a defective cell envelope. We report that loss of yhcB , a conserved gene of unknown function, results in loss of envelope stability, increased cell permeability and dysregulated control of cell size. Using whole genome transposon mutagenesis strategies, we report the comprehensive genetic interaction network of yhcB , revealing all genes with a synthetic negative and a synthetic positive relationship. These genes include those previously reported to have a role in cell envelope biogenesis. Surprisingly, we identified genes previously annotated as essential that became non-essential in a Δ yhcB background. Subsequent analyses suggest that YhcB functions at the junction of several envelope biosynthetic pathways coordinating the spatiotemporal growth of the cell, highlighting YhcB as an as yet unexplored antimicrobial target.
Publisher: IEEE
Date: 10-2017
DOI: 10.1109/LCN.2017.63
Publisher: Springer Science and Business Media LLC
Date: 08-06-2023
DOI: 10.1038/S41429-023-00629-8
Abstract: The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R& D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R& D and to ensure that plans to address late-stage pipeline issues succeed.
Publisher: MDPI AG
Date: 04-2021
DOI: 10.3390/MOLECULES26072019
Abstract: In the study, two novel compounds along with two new compounds were isolated from Grewia optiva. The novel compounds have never been reported in any plant source, whereas the new compounds are reported for the first time from the studied plant. The four compounds were characterized as: 5,5,7,7,11,13-hexamethyl-2-(5-methylhexyl)icosahydro-1H-cyclopenta[a]chrysen-9-ol (IX), docosanoic acid (X), methanetriol mano formate (XI) and 2,2’-(1,4-phenylene)bis(3-methylbutanoic acid (XII). The anticholinesterase, antidiabetic, and antioxidant potentials of these compounds were determined using standard protocols. All the isolated compounds exhibited a moderate-to-good degree of activity against acetylcholinesterases (AChE) and butyrylcholinesterase (BChE). However, compound XII was particularly effective with IC50 of 55 μg/mL (against AChE) and 60 μg/mL (against BChE), and this inhibitory activity is supported by in silico docking studies. The same compound was also effective against DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid) radicals with IC50 values of 60 and 62 μg/mL, respectively. The compound also significantly inhibited the activities of α-amylase and α-glucosidase in vitro. The IC50 values for inhibition of the two enzymes were recorded as 90 and 92 μg/mL, respectively. The in vitro potentials of compound XII to treat Alzheimer’s disease (in terms of AchE and BChE inhibition), diabetes (in terms of α-amylase and α-glucosidase inhibition), and oxidative stress (in terms of free radical scavenging) suggest further in vivo investigations of the compound for assessing its efficacy, safety profile, and other parameters to proclaim the compound as a potential drug candidate.
Publisher: Elsevier BV
Date: 08-2015
Publisher: Cold Spring Harbor Laboratory
Date: 28-04-2018
DOI: 10.1101/309674
Abstract: Polymyxin B and E (colistin) have been pivotal in the treatment of extensively drug-resistant (XDR) Gram-negative bacterial infections, with increasing use over the past decade. Unfortunately, resistance to these antibiotics is rapidly emerging. The structurally-related octapeptin C4 (OctC4) has shown significant potency against XDR bacteria, including against polymyxin-resistant (Pmx-R) strains, but its mode of action remains undefined. We sought to compare and contrast the acquisition of XDR Klebsiella pneumoniae (ST258) resistance in vitro with all three lipopeptides to help elucidate the mode of action of the drugs and potential mechanisms of resistance evolution. Strikingly, 20 days of exposure to the polymyxins resulted in a dramatic (1000-fold) increase in the minimum inhibitory concentration (MIC) for the polymyxins, reflecting the evolution of resistance seen in clinical isolates, whereas for OctC4 only a 4-fold increase was witnessed. There was no cross-resistance observed between the polymyxin - and octapeptin-induced resistant strains. Sequencing revealed previously known gene alterations for polymyxin resistance, including crrB , mgrB , pmrB , phoPQ and yciM , and novel mutations in qseC . In contrast, mutations in mlaDF and pqiB , 1genes related to phospholipid transport, were found in octapeptin-resistant isolates. Mutation effects were validated via complementation assays. These genetic variations were reflected in phenotypic changes to lipid A. Pmx-R isolates increased 4-amino-4-deoxy-arabinose fortification to phosphate groups of lipid A, whereas OctC4 induced strains harbored a higher abundance of hydroxymyristate and palmitoylate. The results reveal a differing mode of action compared to polymyxins which provides hope for future therapeutics to combat the increasingly threat of XDR bacteria.
Publisher: American Chemical Society (ACS)
Date: 12-06-2020
Publisher: Elsevier BV
Date: 02-2001
Publisher: American Chemical Society (ACS)
Date: 30-07-2020
DOI: 10.26434/CHEMRXIV.12736505
Abstract: Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it stands to reason to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad spectrum antifungal activity. Some of these complexes (1-3) show minimum inhibitory concentrations (MIC) in the low micro- to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report first in vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266 mg/kg are tolerated without adverse effects, paving the way for further in vivo studies of these complexes. br
Publisher: Springer Science and Business Media LLC
Date: 04-09-2013
DOI: 10.1038/JA.2013.86
Abstract: The continued emergence of multi-drug-resistant bacteria is a major public health concern. The identification and development of new antibiotics, especially those with new modes of action, is imperative to help treat these infections. This review lists the 22 new antibiotics launched since 2000 and details the two first-in-class antibiotics, fidaxomicin (1) and bedaquiline (2), launched in 2011 and 2012, respectively. The development status, mode of action, spectra of activity, historical discovery and origin of the drug pharmacophore (natural product, natural product derived, synthetic or protein/mammalian peptide) of the 49 compounds and 6 β-lactamase/β-lactam combinations in active clinical development are discussed, as well as compounds that have been discontinued from clinical development since 2011. New antibacterial pharmacophore templates are also reviewed and analyzed.
Publisher: American Chemical Society (ACS)
Date: 05-11-2020
Publisher: Elsevier BV
Date: 03-2018
Publisher: American Chemical Society (ACS)
Date: 09-08-2019
Publisher: Elsevier BV
Date: 04-2018
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3OB42428F
Abstract: Dalbavancin, a semi-synthetic glycopeptide with enhanced antibiotic activity compared to vancomycin and teicoplanin, dimerises strongly in an anti-cooperative manner with ligand binding.
Publisher: Informa UK Limited
Date: 03-06-2018
Publisher: American Society for Microbiology
Date: 10-2015
DOI: 10.1128/AAC.00808-15
Abstract: Colistin has found increasing use in treating drug-resistant bacterial lung infections, but potential interactions with pulmonary biomolecules have not been investigated. We postulated that colistin, like aminoglycoside antibiotics, may bind to secretory mucin in sputum or epithelial mucin that lines airways, reducing free drug levels. To test this hypothesis, we measured binding of colistin and other antibiotics to porcine mucin, a family of densely glycosylated proteins used as a surrogate for human sputum and airway mucin. Antibiotics were incubated in dialysis tubing with or without mucin, and concentrations of unbound antibiotics able to penetrate the dialysis tubing were measured over time using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The percentage of antibiotic measured in the dialysate after 4 h in the presence of mucin, relative to the amount without mucin, was 15% for colistin, 16% for polymyxin B, 19% for tobramycin, 52% for ciprofloxacin, and 78% for daptomycin. Antibiotics with the strongest mucin binding had an overall polybasic positive charge, whereas those with comparatively little binding were less basic. When comparing MICs measured with or without added mucin, colistin and polymyxin B showed -fold increases in MICs for multiple Gram-negative bacteria. Preclinical evaluation of mucin binding should become a standard procedure when considering the potential pulmonary use of new or existing antibiotics, particularly those with a polybasic overall charge. In the airways, mucin binding may reduce the antibacterial efficacy of inhaled or intravenously administered colistin, and the presence of sub-MIC effective antibiotic concentrations could result in the development of antibiotic resistance.
Publisher: American Chemical Society (ACS)
Date: 31-08-2021
Publisher: Portland Press Ltd.
Date: 28-02-2017
DOI: 10.1042/EBC20160077
Abstract: We are facing a potential catastrophe of untreatable bacterial infections, driven by the inexorable rise of extensively drug-resistant bacteria, coupled with a market failure of pharmaceutical and biotech companies to deliver new therapeutic options. While global recognition of the problem is finally apparent, solutions are still a long way from being implemented. In addition to drug stewardship programmes and better diagnostics, new antibiotics are desperately needed. The question remains as to how to achieve this goal. This review will examine the different strategies being applied to discover new antibiotics.
Publisher: MDPI AG
Date: 27-11-2021
DOI: 10.3390/PH14121232
Abstract: We hypothesized that environmental microbiomes contain a wide range of bacteria that produce yet uncharacterized antimicrobial compounds (AMCs) that can potentially be used to control pathogens. Over 600 bacterial strains were isolated from soil and food compost s les, and 68 biocontrol bacteria with antimicrobial activity were chosen for further studies based on inhibition assays against a wide range of food and plant pathogens. For further characterization of the bioactive compounds, a new method was established that used living pathogens in a liquid culture to stimulate bacteria to produce high amounts of AMCs in bacterial supernatants. A peptide gel electrophoresis microbial inhibition assay was used to concurrently achieve size separation of the antimicrobial peptides. Fifteen potential bioactive peptides were then further characterized by tandem MS, revealing cold-shock proteins and 50S ribosomal proteins. To identify non-peptidic AMCs, bacterial supernatants were analyzed by HPLC followed by GC/MS. Among the 14 identified bioactive compounds, 3-isobutylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione and 2-acetyl-3-methyl-octahydropyrrolo[1,2-a]piperazine-1,4-dione were identified as new AMCs. Our work suggests that antimicrobial compound production in microbes is enhanced when faced with a threat from other microorganisms, and that this approach can rapidly lead to the development of new antimicrobials with the potential for upscaling.
Publisher: Elsevier BV
Date: 06-1993
Publisher: Springer Science and Business Media LLC
Date: 23-06-2020
DOI: 10.1038/S41467-020-16950-X
Abstract: Peptide antibiotics are an abundant and synthetically tractable source of molecular ersity, but they are often cationic and can be cytotoxic, nephrotoxic and/or ototoxic, which has limited their clinical development. Here we report structure-guided optimization of an hipathic peptide, arenicin-3, originally isolated from the marine lugworm Arenicola marina . The peptide induces bacterial membrane permeability and ATP release, with serial passaging resulting in a mutation in mlaC , a phospholipid transport gene. Structure-based design led to AA139, an antibiotic with broad-spectrum in vitro activity against multidrug-resistant and extensively drug-resistant bacteria, including ESBL, carbapenem- and colistin-resistant clinical isolates. The antibiotic induces a 3–4 log reduction in bacterial burden in mouse models of peritonitis, pneumonia and urinary tract infection. Cytotoxicity and haemolysis of the progenitor peptide is ameliorated with AA139, and the ‘no observable adverse effect level’ (NOAEL) dose in mice is ~10-fold greater than the dose generally required for efficacy in the infection models.
Publisher: American Chemical Society (ACS)
Date: 23-07-1999
DOI: 10.1021/JO9904718
Publisher: Bentham Science Publishers Ltd.
Date: 08-2012
DOI: 10.2174/156802612802652448
Abstract: Many biologically active compounds are unsuitable for development as drugs due to their poor bioavailability. For hydrophilic compounds, modifications to increase lipophilicity can increase passive diffusion or increase uptake into the lymphatic system. Alternatively, improved bioavailability of hydrophilic drug candidates may be achieved by formulation with absorption promoters such as surfactants, penetration enhancers, or ion pairing agents. This approach to enhancing bioavailability also has the potential to widen the range of compound categories that can be used as chemical probes to study biological systems in cells and in vivo where membrane permeability would otherwise be a significant limitation. Lipidic amino acids, which combine the structural properties of lipids with those of α-amino acids, represent a relatively unexplored class of agents that can improve drug adsorption. This review discusses the potential of absorption promoters possessing lipoamino acids for improving drug bioavailability.
Publisher: MDPI AG
Date: 26-10-2018
DOI: 10.3390/ANTIBIOTICS7040093
Abstract: The use of silver to control infections was common in ancient civilizations. In recent years, this material has resurfaced as a therapeutic option due to the increasing prevalence of bacterial resistance to antimicrobials. This renewed interest has prompted researchers to investigate how the antimicrobial properties of silver might be enhanced, thus broadening the possibilities for antimicrobial applications. This review presents a compilation of patented products utilizing any forms of silver for its bactericidal actions in the decade 2007–2017. It analyses the trends in patent applications related to different forms of silver and their use for antimicrobial purposes. Based on the retrospective view of registered patents, statements of prognosis are also presented with a view to heightening awareness of potential industrial and health care applications.
Publisher: Elsevier BV
Date: 12-2019
Publisher: American Chemical Society (ACS)
Date: 19-07-2022
Publisher: American Chemical Society (ACS)
Date: 28-03-2022
DOI: 10.1021/ACSINFECDIS.1C00660
Abstract: Bacterial infections are a significant cause of mortality and morbidity worldwide, despite decades of use of numerous existing antibiotics and constant efforts by researchers to discover new antibiotics. The emergence of infections associated with antibiotic-resistant bacterial strains, has lified the pressure to develop additional bactericidal therapies or new unorthodox approaches that can deal with antimicrobial resistance. Nanomaterial-based strategies, particularly those that do not rely on conventional small-molecule antibiotics, offer promise in part due to their ability to dodge existing mechanisms used by drug-resistant bacteria. Therefore, the use of nanomaterial-based formulations has attracted attention in the field of antibiotic therapy. In this Review, we highlight novel and emerging nanomaterial-based formulations along with details about the mechanisms by which nanoparticles can target bacterial infections and antimicrobial resistance. A detailed discussion about types and the activities of nanoparticles is presented, along with how they can be used as either delivery systems or as inherent antimicrobials, or a combination of both. Lastly, we highlight some toxicological concerns for the use of nanoparticles in antibiotic therapies.
Publisher: American Chemical Society (ACS)
Date: 13-12-2017
DOI: 10.1021/ACS.BIOCONJCHEM.6B00494
Abstract: Many bacterial pathogens have now acquired resistance toward commonly used antibiotics, such as the glycopeptide antibiotic vancomycin. In this study, we show that immobilization of vancomycin onto a nanometer-scale solid surface with controlled local density can potentiate antibiotic action and increase target affinity of the drug. Magnetic nanoparticles were conjugated with vancomycin and used as a model system to investigate the relationship between surface density and drug potency. We showed remarkable improvement in minimum inhibitory concentration against vancomycin-resistant strains with values of 13-28 μg/mL for conjugated vancomycin compared to 250-4000 μg/mL for unconjugated vancomycin. Higher surface densities resulted in enhanced affinity toward the bacterial target compared to that of unconjugated vancomycin, as measured by a competition experiment using a surrogate ligand for bacterial Lipid II, N-Acetyl-l-Lys-d-Ala-d-Ala. High density vancomycin nanoparticles required >64 times molar excess of ligand (relative to the vancomycin surface density) to abrogate antibacterial activity compared to only 2 molar excess for unconjugated vancomycin. Further, the drug-nanoparticle conjugates caused rapid permeabilization of the bacterial cell wall within 2 h, whereas no effect was seen with unconjugated vancomycin, suggesting additional modes of action for the nanoparticle-conjugated drug. Hence, immobilization of readily available antibiotics on nanocarriers may present a general strategy for repotentiating drugs that act on bacterial membranes or membrane-bound targets but have lost effectiveness against resistant bacterial strains.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9MD00120D
Abstract: The quinolone antibiotics arose in the early 1960s, with the first ex les possessing a narrow-spectrum activity with unfavorable pharmacokinetic properties.
Publisher: American Chemical Society (ACS)
Date: 11-07-2017
Publisher: Bentham Science Publishers Ltd.
Date: 08-2012
DOI: 10.2174/138945012803530251
Abstract: Biofilms formed by pathogenic bacteria present a serious threat to human health as the efficacy of standard antibiotic therapeutic regimens is compromised by reduced microbial susceptibility within the biofilm environment. The discovery of improved therapies for biofilm elimination requires an understanding of biofilm formation and dispersal, and the development of assays to specifically analyze these dynamic processes. This review will discuss biofilm screening strategies suitable for drug discovery efforts, especially chemical and biological approaches that specifically target biofilm destruction.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2023
Publisher: MDPI AG
Date: 18-03-2022
DOI: 10.3390/ANTIBIOTICS11030412
Abstract: The development of effective treatments against infectious diseases is an extensive and ongoing process due to the rapid adaptation of bacteria to antibiotic-based therapies. However, appropriately designed activity enhancers, including antibiotic delivery systems, can increase the effectiveness of current antibiotics, overcoming antimicrobial resistance and decreasing the chance of contributing to further bacterial resistance. The activity/delivery enhancers improve drug absorption, allow targeted antibiotic delivery, improve their tissue and biofilm penetration and reduce side effects. This review provides insights into various antibiotic activity enhancers, including polymer, lipid, and silver-based systems, designed to reduce the adverse effects of antibiotics and improve formulation stability and efficacy against multidrug-resistant bacteria.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2015
DOI: 10.1038/JA.2015.4
Publisher: Elsevier BV
Date: 08-2014
Publisher: F1000 Research Ltd
Date: 11-06-2021
DOI: 10.12688/WELLCOMEOPENRES.16847.1
Abstract: There is an increasingly urgent need for new antibiotics, yet there is a significant and persistent economic problem when it comes to developing such medicines. The problem stems from the perceived need for a “market” to drive commercial antibiotic development. In this article, we explore abandoning the market as a prerequisite for successful antibiotic research and development. Once one stops trying to fix a market model that has stopped functioning, one is free to carry out research and development (R& D) in ways that are more openly collaborative, a mechanism that has been demonstrably effective for the R& D underpinning the response to the COVID pandemic. New “open source” research models have great potential for the development of medicines for areas of public health where the traditional profit-driven model struggles to deliver. New financial initiatives, including major push ull incentives, aimed at fixing the broken antibiotics market provide one possible means for funding an openly collaborative approach to drug development. We argue that now is therefore the time to evaluate, at scale, whether such methods can deliver new medicines through to patients, in a timely manner.
Publisher: American Chemical Society (ACS)
Date: 23-02-2022
Publisher: American Chemical Society (ACS)
Date: 24-01-2018
Publisher: American Chemical Society (ACS)
Date: 09-05-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9SC06460E
Abstract: There is a dire need for new compounds to combat antibiotic resistance: metal complexes might provide the solution. 906 metal complexes were evaluated against dangerous ESKAPE pathogens and found to have a higher hit-rate than organic molecules.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D2MD00465H
Abstract: Antimicrobial resistance (AMR) is a global threat to society due to the increasing emergence of multi-drug resistant bacteria that are not susceptible to our last line of defence antibiotics: new approaches are needed to fight back.
Publisher: American Chemical Society (ACS)
Date: 27-09-2019
DOI: 10.26434/CHEMRXIV.9900875.V1
Abstract: New antibiotics and innovative approaches to kill drug-resistant bacteria are urgently needed. Metal-complexes offer access to potential alternative modes of action and have only sparingly been investigated in antibacterial drug discovery. We have developed a light-activated rhenium complex with activity against drug resistant bacteria. The activity profile against mutant strains combined with assessments of cellular uptake and synergy suggest two distinct modes of action.
Publisher: American Chemical Society (ACS)
Date: 16-10-2019
DOI: 10.26434/CHEMRXIV.9900875.V2
Abstract: New antibiotics and innovative approaches to kill drug-resistant bacteria are urgently needed. Metal-complexes offer access to potential alternative modes of action and have only sparingly been investigated in antibacterial drug discovery. We have developed a light-activated rhenium complex with activity against drug resistant bacteria. The activity profile against mutant strains combined with assessments of cellular uptake and synergy suggest two distinct modes of action.
Publisher: American Chemical Society (ACS)
Date: 03-10-2017
DOI: 10.1021/ACSINFECDIS.7B00123
Abstract: Tachyplesin-1 (TP1 1) is a cationic β-hairpin antimicrobial peptide with a membranolytic mechanism of action. While it possesses broad-spectrum, potent antimicrobial activity, 1 is highly hemolytic against mammalian erythrocytes, which precludes it from further development. In this study, we report a template-based approach to investigate the structure-function and structure-toxicity relationships of each amino acid of 1. We modulated charge and hydrophobicity by residue modification and truncation of the peptide. Antimicrobial activity was then assessed against six key bacterial pathogens and two fungi, with toxicity profiled against mammalian cells. The internal disulfide bridge Cys7-Cys12 of 1 was shown to play an important role in broad-spectrum antimicrobial activity against all pathogenic strains tested. Novel peptides based on the progenitor were then designed, including 5 (TP1[F4A]), 12 (TP1[I11A]), and 19 (TP1[C3A,C16A]). These had 26- to 64-fold improved activity/toxicity indices and show promise for further development. Structural studies of 5 (TP1[F4A]) and 12 (TP1[I11A]) identified a conserved β-hairpin secondary structure motif correlating with their very high stablility in mouse and human plasma. Membrane binding affinity determined by surface plasmon resonance confirmed their selectivity toward bacterial membranes, but the degree of membrane binding did not correlate with the degree of hemolysis, suggesting that other factors may drive toxicity.
Publisher: Oxford University Press (OUP)
Date: 14-11-2018
DOI: 10.1093/JAC/DKY458
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1TB01430G
Abstract: Vancomycin (Van) is a key antibiotic of choice for the treatment of systemic methicillin resistant
Publisher: Wiley
Date: 24-11-2020
Publisher: American Chemical Society (ACS)
Date: 30-03-2015
DOI: 10.1021/JM5016846
Publisher: American Society for Microbiology
Date: 29-06-2022
Abstract: Gram-negative pathogens are a major concern for global public health due to increasing rates of antibiotic resistance and the lack of new drugs. A major contributing factor toward antibiotic resistance in Gram-negative bacteria is their formidable outer membrane, which acts as a permeability barrier preventing many biologically active antimicrobials from reaching the intracellular targets and thus limiting their efficacy.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2009
DOI: 10.2174/092986709788612693
Abstract: Protein tyrosine phosphatases (PTPs) play a critical role in physiological signaling pathways by controlling the level of tyrosine phosphorylation. The past decade has seen a vast increase in both academic and industrial interest in PTPs and their relevance as potential therapeutic targets, with several PTP inhibitors recently entering clinical trials. Despite these developments, there are numerous ex les of failed PTP drug discovery programs, such that PTPs have attained a reputation as 'undruggable' targets. This review attempts to illustrate the many obstacles that must be overcome to successfully develop a PTP drug, ranging from validation of PTPs as therapeutic targets to the difficulties of assessing the true inhibitory nature of apparently well-behaved compounds, along with the need to balance the physiocochemical properties required for active site binding with the characteristics needed for in vivo activity. A number of ex les of structure-based design are presented, along with cautionary tales of PTP inhibitor programs that have failed due to unexpected shortcomings.
Publisher: Wiley
Date: 24-11-2020
Publisher: Springer Science and Business Media LLC
Date: 13-08-2014
DOI: 10.1038/JA.2014.111
Abstract: Glycopeptide antibiotics have been a key weapon in the fight against bacterial infections for over half a century, with the progenitors, vancomycin (1) and teicoplanin (2), still used extensively. The increased occurrence of resistance and the effectiveness of these 'last resort' treatments for Gram-positive infections has led to the discovery and clinical development of second generation, semisynthetic lipoglycopeptide derivatives such as telavancin (3), dalbavancin (4) and oritavancin (5), which all possess broader spectra of activity and improved pharmacokinetic properties. Two of these new antibiotics, telavancin (3) and dalbavancin (4), were approved in the past 5 years and the third, oritavancin (5), is awaiting regulatory approval. In this review, the discovery, development and associated resistance of vancomycin (1) and teicoplanin (2), and semi-synthetic glycopeptides, telavancin (3), dalbavancin (4) and oritavancin (5), are detailed. The clinical implications of glycopeptide resistance, especially vancomycin (1), as well as the future prospects for current glycopeptide drugs and the development of new glycopeptides are discussed.
Publisher: American Chemical Society (ACS)
Date: 14-07-2021
Publisher: Frontiers Media SA
Date: 16-04-2019
Publisher: Springer Science and Business Media LLC
Date: 02-11-2021
DOI: 10.1038/S41467-021-26610-3
Abstract: The Ff family of filamentous bacteriophages infect gram-negative bacteria, but do not cause lysis of their host cell. Instead, new virions are extruded via the phage-encoded pIV protein, which has homology with bacterial secretins. Here, we determine the structure of pIV from the f1 filamentous bacteriophage at 2.7 Å resolution by cryo-electron microscopy, the first near-atomic structure of a phage secretin. Fifteen f1 pIV subunits assemble to form a gated channel in the bacterial outer membrane, with associated soluble domains projecting into the periplasm. We model channel opening and propose a mechanism for phage egress. By single-cell microfluidics experiments, we demonstrate the potential for secretins such as pIV to be used as adjuvants to increase the uptake and efficacy of antibiotics in bacteria. Finally, we compare the f1 pIV structure to its homologues to reveal similarities and differences between phage and bacterial secretins.
Publisher: American Chemical Society (ACS)
Date: 14-05-2018
DOI: 10.1021/ACSINFECDIS.8B00109
Abstract: Antimicrobial resistance is a serious threat to global health. Despite numerous initiatives designed to curb excessive and inappropriate use of antibiotics, a recent report ( Klein et al. ( 2018 ) Proc. Natl. Acad. Sci. U. S. A. , 115 , E3463 ) finds that there was a substantial increase in global antibiotic consumption by humans from 2000 to 2015 and predicts a further 200% increase by 2030. Alarmingly, much of this growth is occurring in "last-resort" antibiotics. The study excludes the extensive use of antibiotics in agriculture and aquaculture. This Viewpoint examines the report's findings and discusses them in the context of other recent developments in antimicrobial resistance.
Publisher: MDPI AG
Date: 16-01-2021
DOI: 10.3390/MOLECULES26020449
Abstract: An effective drug nanocarrier was developed on the basis of a quaternized aminated chitosan (Q-AmCs) derivative for the efficient encapsulation and slow release of the curcumin (Cur)-drug. A simple ionic gelation method was conducted to formulate Q-AmCs nanoparticles (NPs), using different ratios of sodium tripolyphosphate (TPP) as an ionic crosslinker. Various characterization tools were employed to investigate the structure, surface morphology, and thermal properties of the formulated nanoparticles. The formulated Q-AmCs NPs displayed a smaller particle size of 162 ± 9.10 nm, and higher surface positive charges, with a maximum potential of +48.3 mV, compared to native aminated chitosan (AmCs) NPs (231 ± 7.14 nm, +32.8 mV). The Cur-drug encapsulation efficiency was greatly improved and reached a maximum value of 94.4 ± 0.91%, compared to 75.0 ± 1.13% for AmCs NPs. Moreover, the in vitro Cur-release profile was investigated under the conditions of simulated gastric fluid [SGF pH 1.2] and simulated colon fluid [SCF pH 7.4]. For Q-AmCs NPs, the Cur-release rate was meaningfully decreased, and recorded a cumulative release value of 54.0% at pH 7.4, compared to 73.0% for AmCs NPs. The formulated nanoparticles exhibited acceptable biocompatibility and biodegradability. These findings emphasize that Q-AmCs NPs have an outstanding potential for the delivery and slow release of anticancer drugs.
Publisher: Mary Ann Liebert Inc
Date: 07-2017
Abstract: Novel therapeutic approaches are urgently needed to combat nosocomial infections caused by extremely drug-resistant (XDR) "superbugs." This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with selective estrogen receptor modulators (SERMs) against problematic Gram-negative pathogens. In vitro synergistic antibacterial activity of polymyxin B and the SERMs tamoxifen, raloxifene, and toremifene was assessed using the microdilution checkerboard and static time-kill assays against a panel of Gram-negative isolates. Polymyxin B and the SERMs were ineffective when used as monotherapy against polymyxin-resistant minimum inhibitory concentration ([MIC] ≥8 mg/L) Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. However, when used in combination, clinically relevant concentrations of polymyxin B and SERMs displayed synergistic killing against the polymyxin-resistant P. aeruginosa, K. pneumoniae, and A. baumannii isolates as demonstrated by a ≥2-3 log10 decrease in bacterial count (CFU/ml) after 24 hours. The combination of polymyxin B with toremifene demonstrated very potent antibacterial activity against P. aeruginosa biofilms in an artificial sputum media assay. Moreover, polymyxin B combined with toremifene synergistically induced cytosolic green fluorescence protein release, cytoplasmic membrane depolarization, permeabilizing activity in a nitrocefin assay, and an increase of cellular reactive oxygen species from P. aeruginosa cells. In addition, scanning and transmission electron micrographs showed that polymyxin B in combination with toremifene causes distinctive damage to the outer membrane of P. aeruginosa cells, compared with treatments with each compound per se. In conclusion, the combination of polymyxin B and SERMs illustrated a synergistic activity against XDR Gram-negative pathogens, including highly polymyxin-resistant P. aeruginosa isolates, and represents a novel combination therapy strategy for the treatment of infections because of problematic XDR Gram-negative pathogens.
Publisher: Frontiers Media SA
Date: 02-07-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-09-2022
DOI: 10.1126/SCITRANSLMED.ABJ2381
Abstract: Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria ( Staphylococcus aureus and Streptococcus pneumoniae ) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC 90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae , as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.
Publisher: American Chemical Society (ACS)
Date: 23-11-2018
Publisher: American Chemical Society (ACS)
Date: 16-10-2019
DOI: 10.26434/CHEMRXIV.9900875
Abstract: New antibiotics and innovative approaches to kill drug-resistant bacteria are urgently needed. Metal-complexes offer access to potential alternative modes of action and have only sparingly been investigated in antibacterial drug discovery. We have developed a light-activated rhenium complex with activity against drug resistant bacteria. The activity profile against mutant strains combined with assessments of cellular uptake and synergy suggest two distinct modes of action.
Publisher: Springer Science and Business Media LLC
Date: 10-10-2019
DOI: 10.1038/S41598-019-50746-4
Abstract: Acne is a common skin affliction that involves excess sebum production and modified lipid composition, duct blockage, colonization by bacteria, and inflammation. Acne drugs target one or more of these steps, with antibiotics commonly used to treat the microbial infection for moderate to severe cases. Whilst a number of other acne therapies are purported to possess antimicrobial activity, this has been poorly documented in many cases. We conducted a comparative analysis of the activity of common topical acne drugs against the principal etiological agent associated with acne: the aerotolerant anaerobic Gram-positive organism Propionibacterium acnes (recently renamed as Cutibacterium acnes ). We also assessed their impact on other bacteria that could also be affected by topical treatments, including both antibiotic-sensitive and antibiotic-resistant strains, using broth microdilution assay conditions. Drugs designated specifically as antibiotics had the greatest potency, but lost activity against resistant strains. The non-antibiotic acne agents did possess widespread antimicrobial activity, including against resistant strains, but at substantially higher concentrations. Hence, the antimicrobial activity of non-antibiotic acne agents may provide protection against a background of increased drug-resistant bacteria.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.BIOTECHADV.2018.05.004
Abstract: Silver was widely used in medicine to treat bacterial infections in the 19th and early 20th century, up until the discovery and development of the first modern antibiotics in the 1940s, which were markedly more effective. Since then, every new antibiotic introduced to the clinic has led to an associated development of drug resistance. Today, the threat of extensive bacterial resistance to antibiotics has reignited interest in alternative strategies to treat infectious diseases, with silver regaining well-deserved renewed attention. Silver ions are highly disruptive to bacterial integrity and biochemical function, with comparatively minimal toxicity to mammalian cells. This review focuses on the antimicrobial properties of silver and their use in synergistic combination therapy with traditional antibiotic drugs.
Publisher: Wiley
Date: 15-05-2015
DOI: 10.1002/PRP2.148
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.PHYTOCHEM.2013.02.021
Abstract: Chemical investigations of the aerial parts of the Australian plant Eremophila microtheca resulted in the isolation of three serrulatane diterpenoids, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (1), 3,7,8-trihydroxyserrulat-14-en-19-oic acid (2) and 3,19-diacetoxy-8-hydroxyserrulat-14-ene (3) as well as the previously reported compounds verbascoside (4) and jaceosidin (5). Acetylation and methylation of the major serrulatane diterpenoid 2 afforded 3,8-diacetoxy-7-hydroxyserrulat-14-en-19-oic acid (6) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid methyl ester (7), respectively. The antibacterial activity of 1-7 was assessed against a panel of Gram-positive and Gram-negative bacterial isolates. All of the serrulatane compounds exhibited moderate activity against Streptococcus pyogenes (ATCC 12344) with minimum inhibitory concentrations (MICs) ranging from 64-128 μg/mL. Serrulatane 1 demonstrated activity against all Gram-positive bacterial strains (MICs 64-128 μg/mL) except for Enterococcus faecalis and Enterococcus faecium. This is the first report of natural products from E. microtheca.
Publisher: Elsevier BV
Date: 05-1998
Publisher: Informa Healthcare
Date: 06-2002
Publisher: Future Medicine Ltd
Date: 11-2015
DOI: 10.2217/NNM.15.137
Abstract: Aim: To explore the potential of de novo designed cyclic lipopeptides and its linear counterparts as antibacterial agents. Materials & methods: The lipopeptides were synthesized via solid-phase peptide synthesis and the cyclization was achieved by using succinic acid linker. The antimicrobial activities of the lipopeptides were evaluated in vitro against a variety selection of Gram-negative and Gram-positive bacteria including clinical isolates of multidrug-resistant strains. Results: The synthesized lipopeptides were able to self-assemble into nanoparticles in an aqueous environment, with three exhibiting potent antibacterial activity against Gram-positive bacteria, including clinically relevant multidrug-resistant bacteria. Conclusion: The lead compounds have the potential to be developed as new antibacterials that are effective against Gram-positive bacteria, including multidrug-resistant isolates.
Publisher: American Chemical Society (ACS)
Date: 16-09-2022
DOI: 10.1021/ACS.JMEDCHEM.2C00972
Abstract: Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the
Publisher: American Chemical Society (ACS)
Date: 18-06-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3NP00019B
Abstract: All natural products reported to December 2022 active against helminths (nematodes, tapeworms and flukes) that infect livestock and companion animals.
Publisher: Elsevier BV
Date: 05-2021
Publisher: American Chemical Society (ACS)
Date: 21-04-2023
Publisher: Wiley
Date: 24-02-2021
Abstract: Agelaia‐MPI and protonectin are antimicrobial peptides isolated from the wasp Parachartergus fraternus that show antimicrobial and neuroactive activities. Previously, two analogues of these peptides, neuroVAL and protonectin‐F, were designed to reduce nonspecific toxicity and improve potency. Here, the three‐dimensional structures of neuroVAL, protonectin and protonectin‐F were determined by using circular dichroism and NMR spectroscopy. Antibacterial, antifungal, cytotoxic and hemolytic activities were tested for the parent peptides and analogues. All peptides showed moderate antimicrobial activity against Gram‐positive bacteria, with agelaia‐MPI being the most active. Protonectin and protonectin‐F were found to be toxic to cancerous and noncancerous cell lines. Internalization experiments revealed that these peptides accumulate inside both cell types. By contrast, neuroVAL was nontoxic to all tested cells and was able to enter cells without accumulating. In summary, neuroVAL has potential as a nontoxic cell‐penetrating peptide, while protonectin‐F needs further modification to realize its potential as an antitumor peptide.
Publisher: CSIRO Publishing
Date: 2019
DOI: 10.1071/MA19025
Abstract: Australians love antibiotics, with one of the highest rates of human antibiotic usage in the world. Unfortunately, they are being loved to death, as high rates of inappropriate use, both here and around the globe, are contributing to the rise of drug-resistant bacteria against which our current arsenal of antibiotics is becoming increasingly ineffective. In the past, advancements in developing new antibiotics kept pace with developing resistance, but we are now facing a deadly reality where the pipeline of ‘new and improved' antibiotics is rapidly drying up. There are a number of global initiatives attempting to reprime the pipeline, but the exit of major pharmaceutical companies from antibiotic research and the poor financial performance of antibiotic-focused biotechnology companies continues.
Publisher: American Chemical Society (ACS)
Date: 24-04-2020
Publisher: Cold Spring Harbor Laboratory
Date: 15-07-2022
DOI: 10.1101/2022.07.15.500178
Abstract: Quaternary ammonium compounds (QACs) are widely used as active agents in disinfectants, antiseptics, and preservatives. Despite being in use since the 1940s, there remain multiple open questions regarding their detailed mode-of-action and the mechanisms, including phenotypic heterogeneity, that can make bacteria less susceptible to QACs. To facilitate mode-of-action studies, we synthesized a fluorescent analogue of the quaternary ammonium compound benzalkonium chloride, namely N -dodecyl- N,N -dimethyl-[2-[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]ethyl]azanium-iodide (NBD-DDA). NBD-DDA is readily detected by flow cytometry and fluorescence microscopy with standard GFP/FITC-settings, making it suitable for molecular and single-cell studies. NBD-DDA was then used to investigate resistance mechanisms which can be heterogeneous among in idual bacterial cells. Our results reveal that the antimicrobial activity of NBD-DDA against E. coli, S. aureus and P. aeruginosa is comparable to that of benzalkonium chloride (BAC), a widely used QAC. Characteristic time-kill kinetics and increased tolerance of a BAC tolerant E. coli strain against NBD-DDA suggest that the mode of action of NBD-DDA is similar to that of BAC. Leveraging these findings and NBD-DDA’s fluorescent properties, we show that reduced cellular adsorption is responsible for the evolved BAC tolerance in the BAC tolerant E. coli strain. As revealed by confocal laser scanning microscopy (CLSM), NBD-DDA is preferentially localized in the cell envelope of E. coli , which is a primary target of BAC and other QACs. Overall, NBD-DDA’s antimicrobial activity, its fluorescent properties, and its ease of detection render it a powerful tool to study the mode-of-action and the resistance mechanisms of QACs in bacteria.
Publisher: Organic Syntheses
Date: 2002
Publisher: American Chemical Society (ACS)
Date: 22-05-2017
DOI: 10.1021/ACS.JMEDCHEM.7B00143
Abstract: Infectious diseases claim millions of lives every year, but with the advent of drug resistance, therapeutic options to treat infections are inadequate. There is now an urgent need to develop new and effective treatments. Nitroimidazoles are a class of antimicrobial drugs that have remarkable broad spectrum activity against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. While nitroimidazoles were discovered in the 1950s, there has been renewed interest in their therapeutic potential, particularly for the treatment of parasitic infections and tuberculosis. In this review, we summarize different classes of nitroimidazoles that have been described in the literature in the past five years, from approved drugs and clinical candidates to ex les undergoing preclinical or early stage development. The relatively "nonspecific" mode of action and resistance mechanisms of nitromidazoles are discussed, and contemporary strategies to facilitate nitroimidazole drug development are highlighted.
Publisher: Elsevier BV
Date: 06-2003
DOI: 10.1016/S0960-894X(03)00253-1
Abstract: Selective inhibitors of protein tyrosine phosphatases (PTPases) are of great interest as therapeutic agents and research tools. Several phenylalanine derivatives (1, 2) designed as phosphotyrosine mimetics or irreversible active site inhibitors were successfully synthesized, then incorporated into a combinatorial library based on a peptidomimetic beta-strand template.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-11-2020
DOI: 10.1126/SCITRANSLMED.ABB3791
Abstract: The hydroxyquinoline analog PBT2 breaks resistance to polymyxin class antibiotics in polymyxin-resistant Gram-negative bacteria.
Publisher: American Chemical Society (ACS)
Date: 22-10-2019
DOI: 10.26434/CHEMRXIV.9956744
Abstract: There is a dire need for new classes of antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Antibiotic compounds are notorious for not having very “drug-like” chemical structures. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant i S. aureus /i (MRSA). This work reveals the vast ersity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9MD00124G
Abstract: Fluorescent probes derived from the fluoroquinolone antibiotic ciprofloxacin were synthesised using a Cu( i )-catalysed azide–alkyne cycloaddition (CuAAC) to link a ciprofloxacin azide derivative with alkyne-substituted green and blue fluorophores.
Publisher: American Chemical Society (ACS)
Date: 23-09-2022
Publisher: American Society for Microbiology
Date: 19-04-2021
DOI: 10.1128/AAC.02443-20
Publisher: MDPI AG
Date: 22-03-2022
DOI: 10.3390/MOLECULES27072050
Abstract: Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed % inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing % inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus.
Publisher: Cold Spring Harbor Laboratory
Date: 21-07-2021
DOI: 10.1101/2021.07.20.453082
Abstract: The Ff family of filamentous bacteriophages infect gram-negative bacteria, but do not cause lysis of their host cell. Instead, new virions are extruded via the phage-encoded pIV protein, which has homology with bacterial secretins. Here, we determine the structure of pIV from the f1 filamentous bacteriophage at 2.7 Å resolution by cryo-electron microscopy, the first near-atomic structure of a phage secretin. Fifteen f1 pIV subunits assemble to form a gated channel in the bacterial outer membrane, with associated soluble domains projecting into the periplasm. We model channel opening and propose a mechanism for phage egress. By single-cell microfluidics experiments, we demonstrate the potential for secretins such as pIV to be used as adjuvants to increase the uptake and efficacy of antibiotics in bacteria. Finally, we compare the f1 pIV structure to its homologues to reveal similarities and differences between phage and bacterial secretins.
Publisher: American Chemical Society (ACS)
Date: 30-07-2020
DOI: 10.26434/CHEMRXIV.12736505.V1
Abstract: Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it stands to reason to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad spectrum antifungal activity. Some of these complexes (1-3) show minimum inhibitory concentrations (MIC) in the low micro- to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report first in vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266 mg/kg are tolerated without adverse effects, paving the way for further in vivo studies of these complexes.
Publisher: Cold Spring Harbor Laboratory
Date: 18-04-2021
DOI: 10.1101/2021.04.16.440158
Abstract: The cell envelope is essential for viability in all kingdoms of life. It retains enzymes and substrates within a confined space while providing a protective barrier to the external environment. Destabilising the envelope of bacterial pathogens is a common strategy employed by antimicrobial treatment. However, even in one of the most well studied organisms, Escherichia coli , there remain gaps in our understanding of how the synthesis of the successive layers of the cell envelope are coordinated during growth and cell ision. Here, we used a whole genome phenotypic screen to identify mutants with a defective cell envelope. We report that loss of yhcB , a conserved gene of unknown function, results in loss of envelope stability, increased cell permeability and dysregulated control of cell size. Using whole genome transposon mutagenesis strategies we report the complete genetic interaction network of yhcB , revealing all genes with a synthetic negative and a synthetic positive relationship. These genes include those previously reported to have a role in cell envelope biogenesis. Surprisingly, we identified genes previously annotated as essential that became non-essential in a Δ yhcB background. Subsequent analyses suggest that YhcB sits at the junction of several envelope biosynthetic pathways coordinating the spatiotemporal growth of the cell, highlighting YhcB as an as yet unexplored antimicrobial target.
Publisher: American Chemical Society (ACS)
Date: 17-04-2013
DOI: 10.1021/CM4005745
Publisher: Bentham Science Publishers Ltd.
Date: 2008
Publisher: Elsevier BV
Date: 09-1998
DOI: 10.1016/S0960-894X(98)00420-X
Abstract: The general approach of using a bicyclic template to produce inhibitors of the protease superfamily of enzymes has been investigated. The Diels Alder cycloaddition reaction on solid support has been found to be highly efficient for the synthesis of libraries of compounds that mimic the beta-strand secondary structure of proteins. Several potent and selective inhibitors of proteases have been discovered.
Publisher: American Chemical Society (ACS)
Date: 13-05-2016
DOI: 10.1021/ACSINFECDIS.5B00044
Abstract: The world is facing a crisis in treating infectious diseases, with a scarcity of new antibiotics in development to treat the growing threat of drug-resistant "superbugs". We need new strategies to reinvigorate the antibiotic pipeline. In this Viewpoint we discuss one such approach, encouraging the community of synthetic chemists to participate in testing chemical ersity from their laboratories for antimicrobial potential. CO-ADD, the Community for Open Antimicrobial Drug Discovery, offers free screening against five bacteria and two fungi with follow up hit confirmation and validation, all with no strings attached.
Publisher: Oxford University Press (OUP)
Date: 02-2020
DOI: 10.1093/GIGASCIENCE/GIAA002
Abstract: Klebsiella pneumoniae frequently harbours multidrug resistance, and current diagnostics struggle to rapidly identify appropriate antibiotics to treat these bacterial infections. The MinION device can sequence native DNA and RNA in real time, providing an opportunity to compare the utility of DNA and RNA for prediction of antibiotic susceptibility. However, the effectiveness of bacterial direct RNA sequencing and base-calling has not previously been investigated. This study interrogated the genome and transcriptome of 4 extensively drug-resistant (XDR) K. pneumoniae clinical isolates however, further antimicrobial susceptibility testing identified 3 isolates as pandrug-resistant (PDR). The majority of acquired resistance (≥75%) resided on plasmids including several megaplasmids (≥100 kb). DNA sequencing detected most resistance genes (≥70%) within 2 hours of sequencing. Neural network–based base-calling of direct RNA achieved up to 86% identity rate, although ≤23% of reads could be aligned. Direct RNA sequencing (with ∼6 times slower pore translocation) was able to identify (within 10 hours) ≥35% of resistance genes, including those associated with resistance to aminoglycosides, β-lactams, trimethoprim, and sulphonamide and also quinolones, rif icin, fosfomycin, and phenicol in some isolates. Direct RNA sequencing also identified the presence of operons containing up to 3 resistance genes. Polymyxin-resistant isolates showed a heightened transcription of phoPQ (≥2-fold) and the pmrHFIJKLM operon (≥8-fold). Expression levels estimated from direct RNA sequencing displayed strong correlation (Pearson: 0.86) compared to quantitative real-time PCR across 11 resistance genes. Overall, MinION sequencing rapidly detected the XDR/PDR K. pneumoniae resistome, and direct RNA sequencing provided accurate estimation of expression levels of these genes.
Start Date: 06-2022
End Date: 06-2022
Amount: $640,878.00
Funder: Australian Research Council
View Funded ActivityStart Date: 07-2021
End Date: 06-2023
Amount: $1,350,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 07-2023
End Date: 07-2028
Amount: $4,508,426.00
Funder: Australian Research Council
View Funded ActivityStart Date: 02-2023
End Date: 02-2024
Amount: $1,078,770.00
Funder: Australian Research Council
View Funded Activity