Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention.
To slow the inexorable rise of antibiotic resistance we must understand how drugs impact on pathogenesis and influence the selection of resistant clones. Staphylococcus aureus is an important human pathogen with populations of antibiotic-resistant bacteria in hospitals and the community. Host phagoc...
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| Format: | Article |
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Public Library of Science (PLoS)
2014-02-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003959&type=printable |
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| author | Gareth McVicker Tomasz K Prajsnar Alexander Williams Nelly L Wagner Michael Boots Stephen A Renshaw Simon J Foster |
| author_facet | Gareth McVicker Tomasz K Prajsnar Alexander Williams Nelly L Wagner Michael Boots Stephen A Renshaw Simon J Foster |
| author_sort | Gareth McVicker |
| collection | DOAJ |
| description | To slow the inexorable rise of antibiotic resistance we must understand how drugs impact on pathogenesis and influence the selection of resistant clones. Staphylococcus aureus is an important human pathogen with populations of antibiotic-resistant bacteria in hospitals and the community. Host phagocytes play a crucial role in controlling S. aureus infection, which can lead to a population "bottleneck" whereby clonal expansion of a small fraction of the initial inoculum founds a systemic infection. Such population dynamics may have important consequences on the effect of antibiotic intervention. Low doses of antibiotics have been shown to affect in vitro growth and the generation of resistant mutants over the long term, however whether this has any in vivo relevance is unknown. In this work, the population dynamics of S. aureus pathogenesis were studied in vivo using antibiotic-resistant strains constructed in an isogenic background, coupled with systemic models of infection in both the mouse and zebrafish embryo. Murine experiments revealed unexpected and complex bacterial population kinetics arising from clonal expansion during infection in particular organs. We subsequently elucidated the effect of antibiotic intervention within the host using mixed inocula of resistant and sensitive bacteria. Sub-curative tetracycline doses support the preferential expansion of resistant microorganisms, importantly unrelated to effects on growth rate or de novo resistance acquisition. This novel phenomenon is generic, occurring with methicillin-resistant S. aureus (MRSA) in the presence of β-lactams and with the unrelated human pathogen Pseudomonas aeruginosa. The selection of resistant clones at low antibiotic levels can result in a rapid increase in their prevalence under conditions that would previously not be thought to favor them. Our results have key implications for the design of effective treatment regimes to limit the spread of antimicrobial resistance, where inappropriate usage leading to resistance may reduce the efficacy of life-saving drugs. |
| format | Article |
| id | doaj-art-2ea585a4bab64a819d37ea30f9cdbf15 |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2014-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-2ea585a4bab64a819d37ea30f9cdbf152025-08-20T03:10:07ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-02-01102e100395910.1371/journal.ppat.1003959Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention.Gareth McVickerTomasz K PrajsnarAlexander WilliamsNelly L WagnerMichael BootsStephen A RenshawSimon J FosterTo slow the inexorable rise of antibiotic resistance we must understand how drugs impact on pathogenesis and influence the selection of resistant clones. Staphylococcus aureus is an important human pathogen with populations of antibiotic-resistant bacteria in hospitals and the community. Host phagocytes play a crucial role in controlling S. aureus infection, which can lead to a population "bottleneck" whereby clonal expansion of a small fraction of the initial inoculum founds a systemic infection. Such population dynamics may have important consequences on the effect of antibiotic intervention. Low doses of antibiotics have been shown to affect in vitro growth and the generation of resistant mutants over the long term, however whether this has any in vivo relevance is unknown. In this work, the population dynamics of S. aureus pathogenesis were studied in vivo using antibiotic-resistant strains constructed in an isogenic background, coupled with systemic models of infection in both the mouse and zebrafish embryo. Murine experiments revealed unexpected and complex bacterial population kinetics arising from clonal expansion during infection in particular organs. We subsequently elucidated the effect of antibiotic intervention within the host using mixed inocula of resistant and sensitive bacteria. Sub-curative tetracycline doses support the preferential expansion of resistant microorganisms, importantly unrelated to effects on growth rate or de novo resistance acquisition. This novel phenomenon is generic, occurring with methicillin-resistant S. aureus (MRSA) in the presence of β-lactams and with the unrelated human pathogen Pseudomonas aeruginosa. The selection of resistant clones at low antibiotic levels can result in a rapid increase in their prevalence under conditions that would previously not be thought to favor them. Our results have key implications for the design of effective treatment regimes to limit the spread of antimicrobial resistance, where inappropriate usage leading to resistance may reduce the efficacy of life-saving drugs.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003959&type=printable |
| spellingShingle | Gareth McVicker Tomasz K Prajsnar Alexander Williams Nelly L Wagner Michael Boots Stephen A Renshaw Simon J Foster Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention. PLoS Pathogens |
| title | Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention. |
| title_full | Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention. |
| title_fullStr | Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention. |
| title_full_unstemmed | Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention. |
| title_short | Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention. |
| title_sort | clonal expansion during staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003959&type=printable |
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