ORCID Profile
0000-0003-3801-6166
Current Organisation
University of Western Australia
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Publisher: MDPI AG
Date: 21-01-2021
DOI: 10.3390/ANTIBIOTICS10020103
Abstract: While antimicrobial resistance (AMR) is seen in both Neisseria gonorrhoeae and Neisseria meningitidis, the former has become resistant to commonly available over-the-counter antibiotic treatments. It is imperative then to develop new therapies that combat current AMR isolates whilst also circumventing the pathways leading to the development of AMR. This review highlights the growing research interest in developing anti-virulence therapies (AVTs) which are directed towards inhibiting virulence factors to prevent infection. By targeting virulence factors that are not essential for gonococcal survival, it is hypothesized that this will impart a smaller selective pressure for the emergence of resistance in the pathogen and in the microbiome, thus avoiding AMR development to the anti-infective. This review summates the current basis of numerous anti-virulence strategies being explored for N. gonorrhoeae.
Publisher: Springer Singapore
Date: 24-09-2017
Publisher: Public Library of Science (PLoS)
Date: 26-07-2023
DOI: 10.1371/JOURNAL.PONE.0287973
Abstract: Fluoroquinolone (FQ) is a potent antibiotic class. However, resistance to this class emerges quickly which hinders its application. In this study, mechanisms leading to the emergence of multidrug-resistant (MDR) Staphylococcus aureus ( S . aureus ) strains under FQ exposure were investigated. S . aureus ATCC 29213 was serially exposed to ciprofloxacin (CIP), ofloxacin (OFL), or levofloxacin (LEV) at sub-minimum inhibitory concentrations (sub-MICs) for 12 days to obtain S . aureus -1 strains and antibiotic-free cultured for another 10 days to obtain S . aureus -2 strains. The whole genome (WGS) and target sequencing were applied to analyze genomic alterations and RT-qPCR was used to access the expressions of efflux-related genes, alternative sigma factors, and genes involved in FQ resistance. A strong and irreversible increase of MICs was observed in all applied FQs (32 to 128 times) in all S . aureus -1 and remained 16 to 32 times in all S . aureus -2. WGS indicated 10 noticeable mutations occurring in all FQ-exposed S . aureus including 2 insdel mutations in SACOL0573 and rimI a synonymous mutation in hslO and 7 missense mutations located in an untranslated region. GrlA, was found mutated (R570H) in all S . aureus -1 and -2. Genes encoding for efflux pumps and their regulator ( norA , norB , norC , and mgrA ) alternative sigma factors ( sigB and sigS ) acetyltransferase ( rimI ) methicillin resistance ( fmtB ) and hypothetical protein BJI72_0645 were overexpressed in FQ-exposed strains. The emergence of MDR S . aureus was associated with the mutations in the FQ-target sequences and the overexpression of efflux pump systems and their regulators.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.JGAR.2016.11.003
Abstract: The aim of this study was to compare global protein expression changes during fluoroquinolone (FQ) exposure of Staphylococcus aureus. Total protein extracts of wild-type S. aureus ATCC 29213 and six multidrug-resistant (MDR) strains derived from the wild-type under different FQ exposures were analysed using the 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) method combined with LC-MS/MS analysis. Differentially expressed proteins were searched for their Gene Ontology (GO) annotation (UniProt database) and protein-protein interaction network (STRING v.10.0). recA expression was determined by real-time quantitative reverse transcription PCR (qRT-PCR) analysis. Overall, 582 unique proteins were identified at a confidence level of >95% (unused cut-off >1.3). After strict filtering for proteins with significant expression changes in comparison with the wild-type S. aureus ATCC 29213, 147 unique proteins were identified. GO searching showed that development of FQ resistance was associated with altered expression of various proteins involved in the SOS response (RecA), antibiotic resistance (MgrA), pathogenesis (uncharacterised leukocidin-like proteins 1 and 2, immunoglobulin-binding protein Sbi, triosephosphate isomerase, enolase, EsxA, SaeR, SarA, MgrA) and the stress response (alkyl hydroperoxide reductase subunit C, ClpB, ClpC, ClpL, ClpX, HslU, l-lactate dehydrogenase 1 and 2, SAV1710). Network analysis of antibiotic resistance-related proteins identified three major protein clusters involved in metabolic pathways, aminoacyl-tRNA biosynthesis and ribosome structure. qRT-PCR results were consistent with the proteomics data. Development of resistance to multiple drugs, including FQs, under drug exposure mostly involves upregulation of SOS and stress response proteins.
Publisher: Akademiai Kiado Zrt.
Date: 30-05-2017
Abstract: The modulation of efflux pump functions under fluoroquinolone (FQ) exposure is of great concern as it could result in occurrence of multidrug-resistant (MDR) bacterial strains. In this study, MDR mechanism in Pseudomonas aeruginosa induced via moxifloxacin (MOX) pressure was investigated. After serial MOX [concentration of 0.5 × the minimum inhibitory concentration (MIC)] exposure, the fully susceptible P. aeruginosa ATCC 9027 strain has increased its MIC not only toward MOX (1→128 mg/L) but also to other antibiotics. Furthermore, this MOX-exposed strain did not revert to antibiotic-sensitive phenotype when being cultured in antibiotic-free medium for 12 days. No mutation was observed for FQ-target ( gyrA and parC ) or most investigated efflux regulatory genes ( mexT , mexR , and nalC ) except nfxB in which a 100-bp deletion was found. This associated with the elevated expression of multidrug efflux pump operon ( mexCD-oprJ ) which could directly result in MDR phenotype.
Publisher: MDPI AG
Date: 20-07-2021
Abstract: The World Health Organization (WHO) has placed N. gonorrhoeae on the global priority list of antimicrobial resistant pathogens and is urgently seeking the development of new intervention strategies. N. gonorrhoeae causes 86.9 million cases globally per annum. The effects of gonococcal disease are seen predominantly in women and children and especially in the Australian Indigenous community. While economic modelling suggests that this infection alone may directly cost the USA health care system USD 11.0–20.6 billion, indirect costs associated with adverse disease and pregnancy outcomes, disease prevention, and productivity loss, mean that the overall effect of the disease is far greater still. In this review, we summate the current progress towards the development of a gonorrhea vaccine and describe the clinical trials being undertaken in Australia to assess the efficacy of the current formulation of Bexsero® in controlling disease.
Publisher: Oxford University Press (OUP)
Date: 30-06-2022
DOI: 10.1093/JAC/DKAC204
Abstract: Neisseria gonorrhoeae is an exclusively human pathogen that commonly infects the urogenital tract resulting in gonorrhoea. Empirical treatment of gonorrhoea with antibiotics has led to multidrug resistance and the need for new therapeutics. Inactivation of lipooligosaccharide phosphoethanolamine transferase A (EptA), which attaches phosphoethanolamine to lipid A, results in attenuation of the pathogen in infection models. Small molecules that inhibit EptA are predicted to enhance natural clearance of gonococci via the human innate immune response. A library of small-fragment compounds was tested for the ability to enhance susceptibility of the reference strain N. gonorrhoeae FA1090 to polymyxin B. The effect of these compounds on lipid A synthesis and viability in models of infection were tested. Three compounds, 135, 136 and 137, enhanced susceptibility of strain FA1090 to polymyxin B by 4-fold. Pre-treatment of bacterial cells with all three compounds resulted in enhanced killing by macrophages. Only lipid A from bacterial cells exposed to compound 137 showed a 17% reduction in the level of decoration of lipid A with phosphoethanolamine by MALDI-TOF MS analysis and reduced stimulation of cytokine responses in THP-1 cells. Binding of 137 occurred with higher affinity to purified EptA than the starting material, as determined by 1D saturation transfer difference NMR. Treatment of eight MDR strains with 137 increased susceptibility to polymyxin B in all cases. Small molecules have been designed that bind to EptA, inhibit addition of phosphoethanolamine to lipid A and can sensitize N. gonorrhoeae to killing by macrophages.
Publisher: MDPI AG
Date: 29-08-2023
DOI: 10.3390/ANTIBIOTICS12091382
Abstract: Antibiotic resistance caused by multidrug-resistant (MDR) bacteria is a major challenge to global public health. Polymyxins are increasingly being used as last-in-line antibiotics to treat MDR Gram-negative bacterial infections, but resistance development renders them ineffective for empirical therapy. The main mechanism that bacteria use to defend against polymyxins is to modify the lipid A headgroups of the outer membrane by adding phosphoethanolamine (PEA) moieties. In addition to lipid A modifying PEA transferases, Gram-negative bacteria possess PEA transferases that decorate proteins and glycans. This review provides a comprehensive overview of the function, structure, and mechanism of action of PEA transferases identified in pathogenic Gram-negative bacteria. It also summarizes the current drug development progress targeting this enzyme family, which could reverse antibiotic resistance to polymyxins to restore their utility in empiric therapy.
No related grants have been discovered for Van Chi Thai.