Prediction of Fluoroquinolone Susceptibility Directly from Whole-Genome Sequence Data by Using Liquid Chromatography-Tandem Mass Spectrometry To Identify Mutant Genotypes.
Wan Ahmad Kamil Wan Nur Ismah,Wan Ahmad Kamil Wan Nur Ismah,Yuiko Takebayashi,Jacqueline Findlay,Kate J. Heesom,Juan-Carlos Jiménez-Castellanos,Jay Zhang,Lee Graham,Karen E. Bowker,O. Martin Williams,Alasdair P. MacGowan,Alasdair P. MacGowan,Matthew B. Avison +12 more
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TLDR
Improved biological understanding was then used to generate 47 rules that can predict fluoroquinolone susceptibility in K. pneumoniae clinical isolates, and the use of liquid chromatography-tandem mass spectrometry to measure the abundance of proteins in extracts of cultured bacteria revealed which sequence variants seen in the whole-genome sequence data were functionally important in the context of fluoroquolones susceptibility.Abstract:
Fluoroquinolone resistance in Gram-negative bacteria is multifactorial, involving target site mutations, reductions in fluoroquinolone entry due to reduced porin production, increased fluoroquinolone efflux, enzymes that modify fluoroquinolones, and Qnr, a DNA mimic that protects the drug target from fluoroquinolone binding. Here we report a comprehensive analysis, using transformation and in vitro mutant selection, of the relative importance of each of these mechanisms for fluoroquinolone nonsusceptibility using Klebsiella pneumoniae as a model system. Our improved biological understanding was then used to generate 47 rules that can predict fluoroquinolone susceptibility in K. pneumoniae clinical isolates. Key to the success of this predictive process was the use of liquid chromatography-tandem mass spectrometry to measure the abundance of proteins in extracts of cultured bacteria, identifying which sequence variants seen in the whole-genome sequence data were functionally important in the context of fluoroquinolone susceptibility.read more
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Proteomics approach to understand bacterial antibiotic resistance strategies.
Bo Peng,Hui Li,Xuan-xian Peng +2 more
TL;DR: The authors summarize the recent progress on antibiotic resistance caused by lab-evolved bacteria and clinical multidrug-resistant bacterial pathogens from the proteomics perspective.
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Characterization of AmpC-hyperproducing Escherichia coli from humans and dairy farms collected in parallel in the same geographical region
Maryam Alzayn,Maryam Alzayn,Jacqueline Findlay,Hannah Schubert,Oliver Mounsey,Virginia C. Gould,Kate J. Heesom,Katy Turner,David C Barrett,Kristen K. Reyher,Matthew B. Avison +10 more
TL;DR: Clear evidence was found for recent farm-to-farm transmission of AmpC-hyperproducing E. coli and of adaptive mutations to expand resistance, and efforts to reduce third-generation cephalosporin resistance on dairy farms must address the high prevalence of ampC hyperproducers.
Posted ContentDOI
Prediction of cephalosporin and carbapenem susceptibility in multi-drug resistant Gram-negative bacteria using liquid chromatography-tandem mass spectrometry
Yuiko Takebayashi,Wak Nur Ismah Wan,Jacqueline Findlay,Kate J. Heesom,Jiaxiang Zhang,OM Williams,Alasdair P. MacGowan,Matthew B. Avison +7 more
TL;DR: A robust and tractable methodology that allows measurement of the abundance of key proteins responsible for antibacterial drug resistance within samples of 1 µg of total bacterial protein is reported, allowing correct prediction of β-lactam susceptibility in clinical isolates from four key bacterial species.
Journal ArticleDOI
Mutation of kvrA Causes OmpK35 and OmpK36 Porin Downregulation and Reduced Meropenem-Vaborbactam Susceptibility in KPC-Producing Klebsiella pneumoniae.
Punyawee Dulyayangkul,Wan Ahmad Kamil Wan Nur Ismah,Wan Ahmad Kamil Wan Nur Ismah,Edward J. A. Douglas,Matthew B. Avison +4 more
TL;DR: It is demonstrated that KvrA loss reduces OMPK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem-vaborbactam in a KPC-3-producing K. pneumoniae isolate.
Journal ArticleDOI
Impact of OqxR loss of function on the envelope proteome of Klebsiella pneumoniae and susceptibility to antimicrobials
Wan Ahmad Kamil Wan Nur Ismah,Wan Ahmad Kamil Wan Nur Ismah,Yuiko Takebayashi,Jacqueline Findlay,Kate J. Heesom,Matthew B. Avison +5 more
TL;DR: The relative effects of OqxR and RamR loss-of-function mutations on envelope protein production, envelope permeability and antimicrobial susceptibility are defined and only RamR mutants have significantly reduced β- lactamase-mediated β-lactam susceptibility and therefore represent a greater clinical threat.
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