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Title: Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR.
Austin Authors: Howden, Benjamin P ;McEvoy, Christopher R E;Allen, David L;Chua, Kyra Y L ;Gao, Wei;Harrison, Paul F;Bell, Jan;Coombs, Geoffrey W;Bennett-Wood, Vicki;Porter, Jessica L;Robins-Browne, Roy;Davies, John K;Seemann, Torsten;Stinear, Timothy P
Affiliation: Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia
Infectious Diseases
Issue Date: 10-Nov-2011
Publication information: Plos Pathogens 2011; 7(11): e1002359
Abstract: Antimicrobial resistance in Staphylococcus aureus is a major public health threat, compounded by emergence of strains with resistance to vancomycin and daptomycin, both last line antimicrobials. Here we have performed high throughput DNA sequencing and comparative genomics for five clinical pairs of vancomycin-susceptible (VSSA) and vancomycin-intermediate ST239 S. aureus (VISA); each pair isolated before and after vancomycin treatment failure. These comparisons revealed a frequent pattern of mutation among the VISA strains within the essential walKR two-component regulatory locus involved in control of cell wall metabolism. We then conducted bi-directional allelic exchange experiments in our clinical VSSA and VISA strains and showed that single nucleotide substitutions within either walK or walR lead to co-resistance to vancomycin and daptomycin, and caused the typical cell wall thickening observed in resistant clinical isolates. Ion Torrent genome sequencing confirmed no additional regulatory mutations had been introduced into either the walR or walK VISA mutants during the allelic exchange process. However, two potential compensatory mutations were detected within putative transport genes for the walK mutant. The minimal genetic changes in either walK or walR also attenuated virulence, reduced biofilm formation, and led to consistent transcriptional changes that suggest an important role for this regulator in control of central metabolism. This study highlights the dramatic impacts of single mutations that arise during persistent S. aureus infections and demonstrates the role played by walKR to increase drug resistance, control metabolism and alter the virulence potential of this pathogen.
DOI: 10.1371/journal.ppat.1002359
Journal: Plos Pathogens
Type: Journal Article
Subjects: Animals
Anti-Bacterial Agents.pharmacology.therapeutic use
Bacterial Proteins.genetics.metabolism
Cell Wall.genetics.metabolism
Daptomycin.pharmacology.therapeutic use
Drug Resistance, Multiple, Bacterial.genetics
High-Throughput Nucleotide Sequencing
Microbial Sensitivity Tests
Molecular Typing
Polymorphism, Single Nucleotide
Staphylococcal Infections.drug therapy.microbiology
Staphylococcus aureus.drug effects.genetics.metabolism.pathogenicity
Vancomycin.pharmacology.therapeutic use
Vancomycin Resistance.genetics
Virulence Factors
Appears in Collections:Journal articles

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