title: Evolution of resistance to a last-resort antibiotic in Staphylococcus aureus via bacterial competition.
abstract: Antibiotic resistance is a key medical concern, with antibiotic use likely being an important cause. However, here we describe an alternative route to clinically relevant antibiotic resistance that occurs solely due to competitive interactions among bacterial cells. We consistently observe that isolates of Methicillin-resistant Staphylococcus aureus diversify spontaneously into two distinct, sequentially arising strains. The first evolved strain outgrows the parent strain via secretion of surfactants and a toxic bacteriocin. The second is resistant to the bacteriocin. Importantly, this second strain is also resistant to intermediate levels of vancomycin. This so-called VISA (vancomycin-intermediate S. aureus) phenotype is seen in many hard-to-treat clinical isolates. This strain diversification also occurs during in vivo infection in a mouse model, which is consistent with the fact that both coevolved phenotypes resemble strains commonly found in clinic. Our study shows how competition between coevolving bacterial strains can generate antibiotic resistance and recapitulate key clinical phenotypes.
authors.affiliation: Research Centre for Infectious Diseases (ZINF), University of Würzburg, Würzburg 97080, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Koch
authors.affiliation: Research Centre for Infectious Diseases (ZINF), University of Würzburg, Würzburg 97080, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Yepes
authors.affiliation: Institute for Molecular Infection Biology (IMIB), University of Würzburg, Würzburg 97080, Germany.
authors.forename: Konrad U
authors.initials: KU
authors.lastname: Förstner
authors.affiliation: Research Centre for Infectious Diseases (ZINF), University of Würzburg, Würzburg 97080, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wermser
authors.affiliation: Research Centre for Infectious Diseases (ZINF), University of Würzburg, Würzburg 97080, Germany.
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Stengel
authors.affiliation: Research Centre for Infectious Diseases (ZINF), University of Würzburg, Würzburg 97080, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Modamio
authors.affiliation: Institute for Molecular Infection Biology (IMIB), University of Würzburg, Würzburg 97080, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Ohlsen
authors.affiliation: Department of Zoology, University of Oxford, Oxford OX1 3QU, UK; Oxford Centre for Integrative Systems Biology, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Foster
authors.affiliation: Research Centre for Infectious Diseases (ZINF), University of Würzburg, Würzburg 97080, Germany; Institute for Molecular Infection Biology (IMIB), University of Würzburg, Würzburg 97080, Germany. Electronic address: daniel.lopez@uni-wuerzburg.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lopez
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001430:Bacteriocins / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects; D005075:Biological Evolution; D005260:Female; D055624:Methicillin-Resistant Staphylococcus aureus / Q000145:classification* / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D008807:Mice, Inbred BALB C; D008827:Microbiological Phenomena; D008969:Molecular Sequence Data; D010858:Pigmentation; D016415:Sequence Alignment; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000145:classification / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D014640:Vancomycin