title: Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention.
abstract: 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.
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, United Kingdom ; Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: McVicker
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, United Kingdom ; Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, United Kingdom ; MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Tomasz K
authors.initials: TK
authors.lastname: Prajsnar
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, United Kingdom ; Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, United Kingdom ; MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Williams
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, United Kingdom ; Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, United Kingdom ; Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Nelly L
authors.initials: NL
authors.lastname: Wagner
authors.affiliation: Biosciences, University of Exeter, Cornwall Campus, Penryn, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Boots
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, United Kingdom ; MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Western Bank, Sheffield, United Kingdom ; Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, United Kingdom ; Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foster
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002999:Clone Cells / Q000187:drug effects*; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial / Q000502:physiology*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D011157:Population Dynamics; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D015027:Zebrafish
chemical_list: D000900:Anti-Bacterial Agents