Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR.
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...
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2011
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oai:doaj.org-article:0368cd80d7ff4eb2b613194047802cfc2021-11-18T06:05:08ZEvolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR.1553-73661553-737410.1371/journal.ppat.1002359https://doaj.org/article/0368cd80d7ff4eb2b613194047802cfc2011-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22102812/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Antimicrobial 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.Benjamin P HowdenChristopher R E McEvoyDavid L AllenKyra ChuaWei GaoPaul F HarrisonJan BellGeoffrey CoombsVicki Bennett-WoodJessica L PorterRoy Robins-BrowneJohn K DaviesTorsten SeemannTimothy P StinearPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 11, p e1002359 (2011) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Benjamin P Howden Christopher R E McEvoy David L Allen Kyra Chua Wei Gao Paul F Harrison Jan Bell Geoffrey Coombs Vicki Bennett-Wood Jessica L Porter Roy Robins-Browne John K Davies Torsten Seemann Timothy P Stinear Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR. |
| description |
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. |
| format |
article |
| author |
Benjamin P Howden Christopher R E McEvoy David L Allen Kyra Chua Wei Gao Paul F Harrison Jan Bell Geoffrey Coombs Vicki Bennett-Wood Jessica L Porter Roy Robins-Browne John K Davies Torsten Seemann Timothy P Stinear |
| author_facet |
Benjamin P Howden Christopher R E McEvoy David L Allen Kyra Chua Wei Gao Paul F Harrison Jan Bell Geoffrey Coombs Vicki Bennett-Wood Jessica L Porter Roy Robins-Browne John K Davies Torsten Seemann Timothy P Stinear |
| author_sort |
Benjamin P Howden |
| title |
Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR. |
| title_short |
Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR. |
| title_full |
Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR. |
| title_fullStr |
Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR. |
| title_full_unstemmed |
Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR. |
| title_sort |
evolution of multidrug resistance during staphylococcus aureus infection involves mutation of the essential two component regulator walkr. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/0368cd80d7ff4eb2b613194047802cfc |
| work_keys_str_mv |
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1718424581489819648 |