ORCID Profile
0000-0002-4683-708X
Current Organisation
The Alfred Hospital
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Nanotechnology | Synthetic Biology | Nanobiotechnology | Nanochemistry and Supramolecular Chemistry
Machinery and Equipment not elsewhere classified | Expanding Knowledge in Technology |
Publisher: MDPI AG
Date: 25-01-2021
DOI: 10.3390/JCM10030453
Abstract: Ventricular assist device (VAD)-specific infections, in particular, driveline infections, are a concerning complication of VAD implantation that often results in significant morbidity and even mortality. The presence of a percutaneous driveline at the skin exit-site and in the subcutaneous tunnel allows biofilm formation and migration by many bacterial and fungal pathogens. Biofilm formation is an important microbial strategy, providing a shield against antimicrobial treatment and human immune responses biofilm migration facilitates the extension of infection to deeper tissues such as the pump pocket and the bloodstream. Despite the introduction of multiple preventative strategies, driveline infections still occur with a high prevalence of ~10–20% per year and their treatment outcomes are frequently unsatisfactory. Clinical diagnosis, prevention and management of driveline infections are being targeted to specific microbial pathogens grown as biofilms at the driveline exit-site or in the driveline tunnel. The purpose of this review is to improve the understanding of VAD-specific infections, from basic “bench” knowledge to clinical “bedside” experience, with a specific focus on the role of biofilms in driveline infections.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2020
DOI: 10.1038/S41598-020-72478-6
Abstract: Inspired by the interesting natural antimicrobial properties of honey, biohybrid composite materials containing a low-fouling polymer hydrogel network and an encapsulated antimicrobial peroxide-producing enzyme have been developed. These synergistically combine both passive and active mechanisms for reducing microbial bacterial colonization. The mechanical properties of these materials were assessed using compressive mechanical analysis, which revealed these hydrogels possessed tunable mechanical properties with Young’s moduli ranging from 5 to 500 kPa. The long-term enzymatic activities of these materials were also assessed over a 1-month period using colorimetric assays. Finally, the passive low-fouling properties and active antimicrobial activity against a leading opportunistic pathogen, Staphylococcus epidermidis , were confirmed using bacterial cell counting and bacterial adhesion assays. This study resulted in non-adhesive substrate-permeable antimicrobial materials, which could reduce the viability of planktonic bacteria by greater than 7 logs. It is envisaged these new biohybrid materials will be important for reducing bacterial adherence in a range of industrial applications.
Publisher: American Chemical Society (ACS)
Date: 09-11-2017
Abstract: Antimicrobial polymers appear as a promising alternative to tackle the current development of bacterial resistance against conventional antibiotics as they rely on bacterial membrane disruption. This study investigates the effect of segmentation of hydrophobic and cationic functionalities on antimicrobial polymers over their selectivity between bacteria and mammalian cells. Using RAFT technology, statistical, diblock, and highly segmented multiblock copolymers were synthesized in a controlled manner. Polymers were analyzed by HPLC, and the segmentation was found to have a significant influence on their overall hydrophobicity. In addition, the amount of incorporated cationic comonomer was varied to yield a small library of bioactive macromolecules. The antimicrobial properties of these compounds were probed against pathogenic bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis), and their biocompatibility was tested using hemolysis and erythrocyte aggregation assays, as well as mammalian cell viability assays. In all cases, diblock and multiblock copolymers were found to outperform statistical copolymers, and for polymers with a low content of cationic comonomer, the multiblock showed a tremendously increased selectivity for P. aeruginosa and S. epidermidis compared to its statistical and diblock analogue. This work highlights the remarkable effect of segmentation on both the physical properties of the materials as well as their interaction with biological systems. Due to the outstanding selectivity of multiblock copolymers toward certain bacteria strains, the presented materials are a promising platform for the treatment of infections and a valuable tool to combat antimicrobial resistance.
Publisher: American Chemical Society (ACS)
Date: 11-08-2200
Publisher: Oxford University Press (OUP)
Date: 29-04-2010
DOI: 10.1093/JAC/DKQ119
Abstract: (i) To evaluate the role of the adherent growth mode and extracellular polymer substance build-up in biofilm resistance to antibiotics. (ii) To re-assess various mechanisms leading to biofilm resistance to antibiotics. We compared the biofilm MICs, biofilm MBCs using the viable count method, biofilm MBCs based on broth recovery methods and minimum biofilm eradication concentrations (MBECs) of antistaphylococcal antibiotics for multilayer biofilms formed by 'biofilm-positive' S. epidermidis strains and monolayer biofilms formed by their 'biofilm-negative' mutants/variants. Bacterial densities and the quantity of persister cells in both multilayer and monolayer biofilms were assessed to evaluate their roles in biofilm resistance. Monolayer and multilayer biofilms presented similar susceptibilities to multiple antibiotics, based on biofilm MIC, broth recovery-based biofilm MBC and MBEC results. Multilayer biofilms demonstrated higher viable count-based MBCs than monolayer biofilms. Both monolayer and multilayer biofilms had very high bacterial densities of approximately 10(11-12) cfu/mL. Persister cells were found in both monolayer and multilayer biofilms, but not in planktonic cultures at log phase. The presence of persister cells in monolayer and multilayer biofilms appeared to be strain and antibiotic dependent. The adherent growth mode, rather than the ability to build up a typical multilayer biofilm structure, contributes to the high resistance of biofilms to antibiotics, and therefore might be the main virulence factor of coagulase-negative staphylococci (CoNS) with respect to antibiotic resistance. The presence of persister cells in CoNS biofilms plays an important role in antibiotic resistance. Growth at high bacterial densities is another significant factor in biofilm resistance.
Publisher: Hindawi Limited
Date: 20-10-2016
DOI: 10.1111/CMI.12674
Abstract: Interactions between fungi and bacteria and their relevance to human health and disease have recently attracted increased attention in biomedical fields. Emerging evidence shows that bacteria and fungi can have synergistic or antagonistic interactions, each with important implications for human colonization and disease. It is now appreciated that some of these interactions may be strategic and helps promote the survival of one or both microorganisms within the host. This review will shed light on clinically relevant interactions between fungi and Gram-negative bacteria. Mechanism of interaction, host immune responses, and preventive measures will also be reviewed.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4PY00652F
Abstract: We report the use of RAFT polymerization to obtain eight cationic methacrylate polymers bearing amine or guanidine pendant groups, while varying the R- and Z-RAFT end-groups.
Publisher: Oxford University Press (OUP)
Date: 21-07-2010
DOI: 10.1093/JAC/DKQ275
Publisher: Wiley
Date: 16-08-2020
Publisher: American Chemical Society (ACS)
Date: 11-02-2020
Publisher: Public Library of Science (PLoS)
Date: 05-04-2012
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0CS00986E
Abstract: Macromolecular entities, such as polymers, peptides, proteins, and hybrid materials thereof, are herein reviewed as promising antibiofilm agents.
Publisher: Springer Science and Business Media LLC
Date: 21-12-2015
DOI: 10.1038/SREP18578
Abstract: Biofilm formation is a major pathogenicity strategy of Staphylococcus epidermidis causing various medical-device infections. Persister cells have been implicated in treatment failure of such infections. We sought to profile bacterial subpopulations residing in S. epidermidis biofilms and to establish persister-targeting treatment strategies to eradicate biofilms. Population analysis was performed by challenging single biofilm cells with antibiotics at increasing concentrations ranging from planktonic minimum bactericidal concentrations (MBCs) to biofilm MBCs (MBC biofilm ). Two populations of “persister cells” were observed: bacteria that survived antibiotics at MBC biofilm for 24/48 hours were referred to as dormant cells those selected with antibiotics at 8 X MICs for 3 hours (excluding dormant cells) were defined as tolerant-but-killable (TBK) cells. Antibiotic regimens targeting dormant cells were tested in vitro for their efficacies in eradicating persister cells and intact biofilms. This study confirmed that there are at least three subpopulations within a S. epidermidis biofilm: normal cells, dormant cells and TBK cells. Biofilms comprise more TBK cells and dormant cells than their log-planktonic counterparts. Using antibiotic regimens targeting dormant cells, i.e . effective antibiotics at MBC biofilm for an extended period, might eradicate S. epidermidis biofilms. Potential uses for this strategy are in antibiotic lock techniques and inhaled aerosolized antibiotics.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.BIOMATERIALS.2013.01.096
Abstract: This work reports the self-assembly of a sparingly soluble antibiotic (ciprofloxacin) and a hydrophobic tripeptide ((D)Leu-Phe-Phe) into supramolecular nanostructures that yield a macroscopic hydrogel at physiological pH. Drug incorporation results in modified morphology and rheological properties of the self-assembled hydrogel. These changes can be correlated with intermolecular interactions between the drug and the peptide, as confirmed by spectroscopic analysis (fluorescence, circular dichroism, IR). The drug appears bound within the hydrogel by non-covalent interactions, and retains its activity over a prolonged release timescale. Antimicrobial activity of the ciprofloxacin-peptide self-assembled hydrogel was evaluated against Staphylococcus aureus, Escherichia coli, and a clinical strain of Klebsiella pneumoniae. Interestingly, the peptide hydrogel alone exhibited a mild anti-bacterial activity against Gram-negative bacteria. While toxic to bacteria, no major cytotoxicity was seen in haemolysis assays of human red blood cells or in mouse fibroblast cell cultures. This new approach of drug incorporation into the nanostructure of a simple tripeptide hydrogel by self-assembly may have important applications for cost-effective wound dressings and novel antimicrobial formulations.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Bentham Science Publishers Ltd.
Date: 24-07-2019
DOI: 10.2174/1386207322666190404145448
Abstract: Assisted reproductive techniques (ART) have been extensively used to treat infertility. Inaccurate prediction of a couple’s fertility often leads to lowered self-esteem for patients seeking ART treatment and causes fertility distress. This prospective study aimed to statistically analyze patient data from a single reproductive medical center over a period of 18 months, and to establish mathematical models that might facilitate accurate prediction of successful pregnancy when ART are used. In the present study, we analyzed clinical data prospectively collected from 760 infertile patients visiting the second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University between June 1, 2016 and December 31, 2017. Various advanced statistical methods, including broken-line regression, were employed to analyze the data. Age remained the most important factor affecting the outcome of IVF/ICSI. Using the broken-line regression model, the fastest clinical pregnancy declining age was between 25 and 32. Female infertility type was found to be a key predictor for the number of good-quality embryos and successful pregnancy, along with the antral follicle count (AFC), total number of embryos, recombinant follicle stimulating hormones (rFSH) dosage, estradiol (E2) on the trigger day, and total number of oocytes retrieved. rFSH dosage was also significantly associated with the number of oocytes retrieved and the number of frozen embryos. The fastest clinical pregnancy declining age is ranged between 25 and 32, and female infertility type is evidenced as another key predictive factor for the cumulative outcome of ART.
Publisher: Frontiers Media SA
Date: 05-06-2020
Publisher: Microbiology Society
Date: 04-2009
Abstract: Coagulase-negative staphylococci (CoNS) are the main causative agents of bacteraemia in infants managed in neonatal intensive care units (NICUs). Intraluminal colonization of long-term central venous catheters by these bacteria and subsequent biofilm formation are the prerequisites of the bloodstream infections acquired in NICUs. The catheter lock technique has been used to treat catheter colonization however, the optimum choice of antimicrobial agents and their corresponding concentrations and exposure times have not been determined. The effectiveness of catheter lock solutions (CLSs) was assessed by determining the minimal biofilm eradication concentration of antimicrobial agents against CoNS biofilms. Five conventional antibiotics (oxacillin, gentamicin, vancomycin, ciprofloxacin and rif icin) alone or in combination, as well as ethanol, were evaluated. Ethanol was found to be superior to all of these conventional antibiotics when used as a CLS. A time–kill study and confocal laser scanning microscopy revealed that exposure to 40 % ethanol for 1 h was sufficient to kill CoNS biofilm cells. To our knowledge, this is the first in vitro study to provide solid evidence to support the rationale of using ethanol at low concentrations for a short time as a CLS, instead of using conventional antibiotics at high concentrations for a long period to treat catheter-related bloodstream infections.
Publisher: Frontiers Media SA
Date: 13-05-2020
Publisher: Springer Science and Business Media LLC
Date: 10-05-2021
DOI: 10.1186/S40635-021-00388-6
Abstract: One of the most serious complications of extracorporeal membrane oxygenation (ECMO) therapy is ECMO cannulae infection, which can occur at quadruple the rate of central venous catheter infections, and significantly impact morbidity and paediatric mortality. The objective of this in vitro observational study was to assess antimicrobial properties of two n -butyl-2-octyl cyanoacrylate tissue adhesive (TA) formulations for bacterial inhibition at peripheral ECMO cannulae insertion sites. Antimicrobial properties were assessed using modified agar disk-diffusion ( n = 3) and simulated agar cannulation insertion site ( n = 20) models. Both assays used Staphylococcus epidermidis which was seeded at the edge of the TA or dressing. Microorganism inhibition was visually inspected and evidenced by the presence or absence of a TA bacterial inhibition zone at 24 and 72 h. Both TAs provided effective barriers to bacterial migration under cannula dressings, to cannula insertion sites and down cannula tunnels. Additionally, both TAs demonstrated distinct zones of inhibition produced when left to polymerise onto agar plates seeded with S. epidermidis . N -Butyl-2-octyl cyanoacrylate TA appears to inhibit bacterial growth and migration of S. epidermidis . Application of TA to cannulae insertion sites may therefore be a potential bedside strategy for infection prevention in ECMO cannulae, but requires further testing before being used clinically for this purpose.
Publisher: American Chemical Society (ACS)
Date: 25-10-2013
DOI: 10.1021/BM401128R
Abstract: We have synthesized a series of copolymers containing both positively charged (amine, guanidine) and hydrophobic side chains ( hiphilic antimicrobial peptide mimics). To investigate the structure-activity relationships of these polymers, low polydispersity polymethacrylates of varying but uniform molecular weight and composition were synthesized, using a reversible addition-fragmentation chain transfer (RAFT) approach. In a facile second reaction, pendant amine groups were converted to guanidines, allowing for direct comparison of cation structure on activity and toxicity. The guanidine copolymers were much more active against Staphylococcus epidermidis and Candida albicans compared to the amine analogues. Activity against Staphylococcus epidermidis in the presence of fetal bovine serum was only maintained for guanidine copolymers. Selectivity for bacterial over mammalian cells was assessed using hemolytic and hemagglutination toxicity assays. Guanidine copolymers of low to moderate molecular weight and hydrophobicity had high antimicrobial activity with low toxicity. Optimum properties appear to be a balance between charge density, hydrophobic character, and polymer chain length. In conclusion, a suite of guanidine copolymers has been identified that represent a new class of antimicrobial polymers with high potency and low toxicity.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2021
DOI: 10.1186/S12906-020-03198-7
Abstract: Pre-administration of probiotic Lactobacilli attenuates ethanol-induced gastric mucosal injury (GMI). The underpinning mechanisms remain to be elucidated. We speculated that lactate, the main metabolite of Lactobacillus that can be safely used as a common food additive, mediated the gastroprotective effect. This study aimed to gain experimental evidence to support our hypothesis and to shed lights on its underlying mechanisms. Lactate was orally administrated to mice at different doses 30 min prior to the induction of GMI. Gastric tissue s les were collected and underwent histopathological and immunohistochemical assessments, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction (qPCR) and western blot analyses. Pretreatment with lactate at 1–3 g/kg significantly curtailed the severity of ethanol-induced GMI, as shown by morphological and histopathological examinations of gastric tissue s les. Significantly lower level of cytokines indicative of local inflammation were found in mice receiving lactate treatment prior to ethanol administration. Western-blot, immunohistochemical analysis and qPCR suggested that gastroprotective properties of lactate were mediated by its modulatory effects on the expression of the apoptosis regulator gene Bax , the apoptotic executive protein gene Casp3 , and genes critical for gastric mucosal integrity, including those encoding tight junction proteins Occludin, Claudin-1, Claudin-5, and that for lactate receptor GPR81. Lactate mitigates ethanol-induced GMI by curtailing local gastric inflammatory response, down-regulating the expression of the apoptosis regulator and executor genes Bax and Casp3 , and up-regulating the expression of genes encoding tight junction proteins Occludin, Claudin-1, and Claudin-5 and the lactate receptor GPR81.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5TB01820J
Abstract: Light triggered release of an antibiotic from a click crosslinked hydrogel was developed by conjugating ciprofloxacin through a photo-cleavable linker to the hydrogel network structure.
Publisher: American Society for Microbiology
Date: 05-2014
Abstract: The fungal pathogen Candida albicans causes macrophage death and escapes, but the molecular mechanisms remained unknown. Here we used live-cell imaging to monitor the interaction of C. albicans with macrophages and show that C. albicans kills macrophages in two temporally and mechanistically distinct phases. Early upon phagocytosis, C. albicans triggers pyroptosis, a proinflammatory macrophage death. Pyroptosis is controlled by the developmental yeast-to-hypha transition of Candida . When pyroptosis is inactivated, wild-type C. albicans hyphae cause significantly less macrophage killing for up to 8 h postphagocytosis. After the first 8 h, a second macrophage-killing phase is initiated. This second phase depends on robust hyphal formation but is mechanistically distinct from pyroptosis. The transcriptional regulator Mediator is necessary for morphogenesis of C. albicans in macrophages and the establishment of the wild-type surface architecture of hyphae that together mediate activation of macrophage cell death. Our data suggest that the defects of the Mediator mutants in causing macrophage death are caused, at least in part, by reduced activation of pyroptosis. A Mediator mutant that forms hyphae of apparently wild-type morphology but is defective in triggering early macrophage death shows a breakdown of cell surface architecture and reduced exposed 1,3 β-glucan in hyphae. Our report shows how Candida uses host and pathogen pathways for macrophage killing. The current model of mechanical piercing of macrophages by C. albicans hyphae should be revised to include activation of pyroptosis by hyphae as an important mechanism mediating macrophage cell death upon C. albicans infection. IMPORTANCE Upon phagocytosis by macrophages, Candida albicans can transition to the hyphal form, which causes macrophage death and enables fungal escape. The current model is that the highly polarized growth of hyphae results in macrophage piercing. This model is challenged by recent reports of C. albicans mutants that form hyphae of wild-type morphology but are defective in killing macrophages. We show that C. albicans causes macrophage cell death by at least two mechanisms. Phase 1 killing (first 6 to 8 h) depends on the activation of the pyroptotic programmed host cell death by fungal hyphae. Phase 2 (up to 24 h) is rapid and depends on robust hyphal formation but is independent of pyroptosis. Our data provide a new model for how the interplay between fungal morphogenesis and activation of a host cell death pathway mediates macrophage killing by C. albicans hyphae.
Publisher: Public Library of Science (PLoS)
Date: 16-10-2015
Publisher: Frontiers Media SA
Date: 13-03-2018
Publisher: Springer Science and Business Media LLC
Date: 27-05-2010
Abstract: Coagulase-negative staphylococci are major causes of bloodstream infections in very low birth weight babies cared for in Neonatal Intensive Care Units. The virulence of these bacteria is mainly due to their ability to form biofilms on indwelling medical devices. Biofilm-related infections often fail to respond to antibiotic chemotherapy guided by conventional antibiotic susceptibility tests. Coagulase-negative staphylococcal blood culture isolates were grown in different phases relevant to biofilm formation: planktonic cells at mid-log phase, planktonic cells at stationary phase, adherent monolayers and mature biofilms and their susceptibilities to conventional antibiotics were assessed. The effects of oxacillin, gentamicin, and vancomycin on preformed biofilms, at the highest achievable serum concentrations were examined. Epifluorescence microscopy and confocal laser scanning microscopy in combination with bacterial viability staining and polysaccharide staining were used to confirm the stimulatory effects of antibiotics on biofilms. Most coagulase-negative staphylococcal clinical isolates were resistant to penicillin G (100%), gentamicin (83.3%) and oxacillin (91.7%) and susceptible to vancomycin (100%), ciprofloxacin (100%), and rif icin (79.2%). Bacteria grown as adherent monolayers showed similar susceptibilities to their planktonic counterparts at mid-log phase. Isolates in a biofilm growth mode were more resistant to antibiotics than both planktonic cultures at mid-log phase and adherent monolayers however they were equally resistant or less resistant than planktonic cells at stationary phase. Moreover, for some cell-wall active antibiotics, concentrations higher than conventional MICs were required to prevent the establishment of planktonic cultures from biofilms. Finally, the biofilm-growth of two S. capitis isolates could be enhanced by oxacillin at the highest achievable serum concentration. We conclude that the resistance of coagulase-negative staphylococci to multiple antibiotics initially remain similar when the bacteria shift from a planktonic growth mode into an early attached mode, then increase significantly as the adherent mode further develops. Furthermore, preformed biofilms of some CoNS are enhanced by oxacillin in a dose-dependent manner.
Publisher: Oxford University Press (OUP)
Date: 14-01-2014
Abstract: Acinetobacter baumannii is one of the most notorious hospital-acquired pathogens, and novel treatment strategies are desperately required. Two-component regulatory systems represent potential therapeutic targets as they mediate microorganism adaptation to changing environments, often control virulence, and are specific to bacteria. Here we describe the first global virulence regulator in A. baumannii. Using transcriptional profiling and functional assays of a deletion mutant in the A. baumannii sensor kinase gene, A1S_0574 (termed as gacS), we show that this sensor kinase regulates key virulence characteristics, including pili synthesis, biofilms, and motility, resulting in virulence attenuation in a mammalian septicemia model. Notably, we also identified that GacS regulates an operon novel to A. baumannii (paa operon), which is responsible for the metabolism of aromatic compounds. Deletion of paaE (A1S_1340) confirmed the role of this operon in A. baumannii virulence. Finally, we identified the cognate response regulator (A1S_0236) for GacS and confirmed their interaction. A1S_0236 was shown to regulate 75% of the GacS transcriptome and the same virulence phenotypes. Overexpression of A1S_0236 restored virulence in the gacS mutant. Our study characterizes a global virulence regulator, which may provide an alternate therapeutic target, in one of the most troublesome hospital-acquired pathogens.
Publisher: Frontiers Media SA
Date: 07-11-2019
Publisher: MDPI AG
Date: 12-10-2023
Publisher: Elsevier BV
Date: 11-2020
DOI: 10.1016/J.HEALUN.2020.07.015
Abstract: Driveline infections remain a major complication of ventricular assist device (VAD) implantation. This study aimed to characterize in vivo microbial biofilms associated with driveline infections and host tissue integration of implanted drivelines. A total of 9 infected and 13 uninfected drivelines were obtained from patients with VAD undergoing heart transplantation in Australia between 2016 and 2018. Each driveline was sectioned into 11 pieces of 1.5 cm in length, and each section was examined by scanning electron microscopy (SEM) and viable counts for microbial biofilms. Microorganisms were cultured and identified. Host tissue integration of clinical drivelines was assessed with micro-computed tomography (CT) and SEM. An in vitro interstitial biofilm assay was used to simulate biofilm migration in the driveline tunnel, and time-lapse microscopy was performed. Of the 9 explanted, infected drivelines, all had organisms isolated from varying depths along the velour section of the drivelines, and all were consistent with the swab culture results of the clinically infected exit site. SEM and micro-CT suggested insufficient tissue integration throughout the driveline velour, with microgaps observed. Clinical biofilms presented as microcolonies within the driveline tunnel, with human tissue as the sub-stratum, and were resistant to anti-microbial treatment. Biofilm migration mediated by a dispersal-seeding mechanism was observed. This study of explanted infected drivelines showed extensive anti-microbial-resistant biofilms along the velour, associated with microgaps between the driveline and the surrounding tissue. These data support the enhancement of tissue integration into the velour as a potential preventive strategy against driveline infections by preventing biofilm migration that may use microgaps as mediators.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.MIMET.2014.05.007
Abstract: The genetic study of mycobacteria, such as Mycobacterium tuberculosis and Mycobacterium ulcerans, is h ered heavily by their slow growth. We have developed efficient, versatile, and improved genetic tools for constructing unmarked recombinant mycobacteria more rapidly including generating multiple mutants using the same antibiotic marker in both fast- and slow-growing mycobacteria.
Publisher: Elsevier
Date: 2018
Publisher: Oxford University Press (OUP)
Date: 21-10-2016
DOI: 10.1093/JAC/DKV334
Abstract: Biofilm-related human infections have high mortality rates due to drug resistance. Cohabitation of erse microbes in polymicrobial biofilms is common and these infections present additional challenges for treatment compared with monomicrobial biofilms. Here, we address this therapeutic gap by assessing the potential of a new class of antimicrobial agents, guanylated polymethacrylates, in the treatment of polymicrobial biofilms built by two prominent human pathogens, the fungus Candida albicans and the bacterium Staphylococcus aureus. We used imaging and quantitative methods to test the antibiofilm efficacy of guanylated polymethacrylates, a new class of drugs that structurally mimic antimicrobial peptides. We further compared guanylated polymethacrylates with first-line antistaphylococcal and anti-Candida agents used as combinatorial therapy against polymicrobial biofilms. Guanylated polymethacrylates were highly effective as a sole agent, killing both C. albicans and S. aureus when applied to established polymicrobial biofilms. Furthermore, they outperformed multiple combinations of current antimicrobial drugs, with one of the tested compounds killing 99.98% of S. aureus and 82.2% of C. albicans at a concentration of 128 mg/L. The extracellular biofilm matrix provided protection, increasing the MIC of the polymethacrylates by 2-4-fold when added to planktonic assays. Using the C. albicans bgl2ΔΔ mutant, we implicate matrix polysaccharide β-1,3 glucan in the mechanism of protection. Data for two structurally distinct polymers suggest that this mechanism could be minimized through chemical optimization of the polymer structure. Finally, we demonstrate that a potential application for these polymers is in antimicrobial lock therapy. Guanylated polymethacrylates are a promising lead for the development of an effective monotherapy against C. albicans/S. aureus polymicrobial biofilms.
Publisher: Frontiers Media SA
Date: 23-11-2020
DOI: 10.3389/FMICB.2020.605608
Abstract: Objectives: In adult ventricular assist device (VAD) programs in Australian hospitals, Medihoney Antibacterial Wound Gel (MAWG) is routinely used at the skin exit-site of VAD drivelines to prevent infections however, its effectiveness remains unclear. Our aim was to assess antimicrobial activity of Medihoney wound gel, using in vitro models that mimic clinical biofilms grown at the driveline exit-site. Methods: Antimicrobial susceptibility testing of MAWG was performed for 24 clinical isolates grown under planktonic conditions, and four representative strains grown as biofilms. Different antimicrobial mechanisms of MAWG were assessed respectively for their relative contribution to its anti-biofilm activity. A colony biofilm assay and a drip-flow biofilm reactor assay mimicking the driveline exit-site environment were used to evaluate the activity of MAWG against biofilm growth at the driveline exit-site. Results: MAWG demonstrated species-specific activity against planktonic cultures [minimum inhibitory concentrations (MICs), 5–20% weight/volume (W/V) for Staphylococcus species, 20–& % (W/V) for Pseudomonas aeruginosa and Candida species]. Higher concentrations [MICs, 30–& % (W/V)] were able to inhibit biofilm growth, but failed to eradicate pre-established biofilms. The anti-biofilm properties of MAWG were multi-faceted, with the often-advertised “active” ingredient methylglyoxal (MGO) playing a less important role. The colony biofilm assay and the drip-flow biofilm reactor assay suggested that MAWG was unable to kill biofilms pre-established in a driveline exit-site environment, or effectively prevent planktonic cells from forming adherent monolayers and further developing mature biofilms. Conclusion: Our work suggests a suboptimal effectiveness of MAWG in preventing driveline infections due to biofilm development.
Publisher: Elsevier BV
Date: 12-2023
Publisher: Frontiers Media SA
Date: 02-07-2021
DOI: 10.3389/FMICB.2021.674502
Abstract: Tigecycline is a last-resort antibiotic for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). This study aimed to broaden our understanding of the acquisition of collateral hypersensitivity by CRKP, as an evolutionary trade-off of developing resistance to tigecycline. Experimental induction of tigecycline resistance was conducted with tigecycline-sensitive CRKP clinical isolates. Antimicrobial susceptibility testing, microbial fitness assessment, genotypic analysis and full-genome sequencing were carried out for these clinical isolates and their resistance-induced descendants. We found that tigecycline resistance was successfully induced after exposing CRKP clinical isolates to tigecycline at gradually increased concentrations, at a minor fitness cost of bacterial cells. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) found higher expression of the efflux pump gene acrB (5.3–64.5-fold) and its regulatory gene ramA (7.4–65.8-fold) in resistance-induced strains compared to that in the tigecycline-sensitive clinical isolates. Stable hypersensitivities to aminoglycosides and other antibiotics were noticed in resistance-induced strains, showing significantly lowered MICs (X 4 – & times). Full genome sequencing and plasmid analysis suggested the induced collateral hypersensitivity might be multifaceted, with the loss of an antimicrobial resistance (AMR) plasmid being a possible major player. This study rationalized the sequential combination of tigecycline with aminoglycosides for the treatment of CRKP infections.
Publisher: Elsevier BV
Date: 12-2023
Publisher: Elsevier BV
Date: 10-2019
Publisher: Springer Science and Business Media LLC
Date: 06-04-2006
DOI: 10.1007/S10096-006-0130-2
Abstract: Selected coagulase-negative staphylococci from the blood of very-low-birth-weight infants in the Neonatal Intensive Care Unit at the Royal Women's Hospital, Melbourne, collected over a 5-year period were examined. Isolates were classified as invasive or contaminants, speciated, typed by pulsed-field gel electrophoresis, and examined for biofilm genes (icaA, icaC, and icaD), adhesion genes (atlE, fbe), and the number of copies of IS256. Of the 24 isolates studied, there were 13 contaminants and 11 invasive isolates. The collection included 15 Staphylococcus epidermidis, eight Staphylococcus capitis, and one each of Staphylococcus warneri and Staphylococcus haemolyticus. Two small clusters of S. epidermidis that belonged to the same molecular type were identified. All S. capitis isolates belonged to the same molecular type or subtype, suggesting that a particular clone was circulating in the unit. There was no significant difference in the species found, the presence of icaA, icaC, icaD, atlE, or fbe, or the number of copies of IS256 between invasive isolates and contaminants. A series of nasal isolates from nonhospitalized adults differed from hospital isolates in the absence of IS256 and the low prevalence of icaC. There was no evidence of IS256-mediated insertion into ica genes as a mechanism of phase variation. These findings suggest that contaminants and invasive isolates derived from the same pool of hospital strains capable of causing sepsis in compromised hosts and that other mechanisms of phase variation exist, apart from IS256 insertion into ica genes.
Publisher: Oxford University Press (OUP)
Date: 08-2012
DOI: 10.1534/GENETICS.112.141432
Abstract: Regulation of the FLO11 adhesin is a model for gene expression control by extracellular signals and developmental switches. We establish that the major mRNA decay pathway regulates FLO11 expression. mRNA deadenylation of transcriptional repressors of FLO11 by the exonuclease Ccr4 keeps their levels low, thereby allowing FLO11 transcription.
Publisher: Proceedings of the National Academy of Sciences
Date: 14-11-2012
Abstract: The controlled biogenesis of mitochondria is a key cellular system coordinated with the cell ision cycle, and major efforts in systems biology currently are directed toward understanding of the control points at which this coordination is achieved. Here we present insights into the function, evolution, and regulation of mitochondrial biogenesis through the study of the protein import machinery in the human fungal pathogen, Candida albicans . Features that distinguish C . albicans from baker’s yeast ( Saccharomyces cerevisiae ) include the stringency of metabolic control at the level of oxygen consumption, the potential for ATP exchange through the porin in the outer membrane, and components and domains in the sorting and assembling machinery complex, a molecular machine that drives the assembly of proteins in the outer mitochondrial membrane. Analysis of targeting sequences and assays of mitochondrial protein import show that components of the electron transport chain are imported by distinct pathways in C. albicans and S. cerevisiae , representing an evolutionary rewiring of mitochondrial import pathways. We suggest that studies using this pathogen as a model system for mitochondrial biogenesis will greatly enhance our knowledge of how mitochondria are made and controlled through the course of the cell- ision cycle.
Publisher: Elsevier BV
Date: 2017
Publisher: Wiley
Date: 16-09-2015
DOI: 10.1002/POLA.27886
Publisher: American Society for Microbiology
Date: 09-2008
DOI: 10.1128/JCM.00592-08
Abstract: Nine Staphylococcus capitis isolates from blood cultures of newborns were examined for resistance to vancomycin. MICs were within the susceptible range, but population profiling revealed a resistant subpopulation. Only isolates with the largest subpopulation were identified as heteroresistant to vancomycin by Etest. This finding may have therapeutic implications.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.JTCVS.2019.02.088
Abstract: Driveline infections remain an important complication of ventricular assist device therapy, with biofilm formation being a major contributor. This study aimed to elucidate factors that govern biofilm formation and migration on clinically relevant ventricular assist device drivelines. Experimental analyses were performed on HeartWare HVAD (HeartWare International Inc, Framingham, Mass) drivelines to assess surface chemistry and biofilm formation. To mimic the driveline exit site, a drip-flow biofilm reactor assay was used. To mimic a subcutaneous tissue environment, a tunnel-based interstitial biofilm assay was developed. Clinical HVAD drivelines explanted at the time of cardiac transplantation were also examined by scanning electron microscopy. Common causative pathogens of driveline infections were able to adhere to the smooth and velour sections of the HVAD driveline and formed robust biofilms in the drip-flow biofilm reactor however, Pseudomonas aeruginosa and Candida albicans had greater biomass. Biofilm migration within the interstitial driveline tunnel was evident for Staphylococcus epidermidis, Staphylococcus aureus, and C albicans, but not P aeruginosa. Biofilm formation by staphylococci was 500 to 10,000 times higher in the tunnel-based model compared with our exit site model. The 3-dimensional structure of the driveline velour and the use of silicone adhesive in driveline manufacturing were found to promote biofilm growth, and explanted patient drivelines demonstrated inadequate tissue in-growth along the entire velour with micro-gaps between velour fibers. This work highlights the predilection of pathogens to different parts of the driveline, the importance of the subcutaneous tunnel to biofilm formation and migration, and the presence of micro-gaps in clinical drivelines that could facilitate invasive driveline infections.
Start Date: 2018
End Date: 2021
Funder: National Natural Science Foundation of China
View Funded ActivityStart Date: 2015
End Date: 2015
Funder: Department of Chemical Engineering, Monash University
View Funded ActivityStart Date: 2014
End Date: 2015
Funder: Monash University
View Funded ActivityStart Date: 2020
End Date: 2021
Funder: Alfred Research Trusts, Alfred Health
View Funded ActivityStart Date: 2020
End Date: 2021
Funder: Medtronic
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: Commonwealth Scientific and Industrial Research Organisation
View Funded ActivityStart Date: 2011
End Date: 2014
Funder: Australian Research Council
View Funded ActivityStart Date: 07-2011
End Date: 09-2015
Amount: $835,200.00
Funder: Australian Research Council
View Funded Activity