title: Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria.
abstract: Bacteria become highly tolerant to antibiotics when nutrients are limited. The inactivity of antibiotic targets caused by starvation-induced growth arrest is thought to be a key mechanism producing tolerance. Here we show that the antibiotic tolerance of nutrient-limited and biofilm Pseudomonas aeruginosa is mediated by active responses to starvation, rather than by the passive effects of growth arrest. The protective mechanism is controlled by the starvation-signaling stringent response (SR), and our experiments link SR-mediated tolerance to reduced levels of oxidant stress in bacterial cells. Furthermore, inactivating this protective mechanism sensitized biofilms by several orders of magnitude to four different classes of antibiotics and markedly enhanced the efficacy of antibiotic treatment in experimental infections.
authors.affiliation: Departments of Medicine, Microbiology and Immunology, McGill University, Montreal, Quebec, Canada. dao.nguyen@mcgill.ca
authors.forename: Dao
authors.initials: D
authors.lastname: Nguyen
authors.forename: Amruta
authors.initials: A
authors.lastname: Joshi-Datar
authors.forename: Francois
authors.initials: F
authors.lastname: Lepine
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bauerle
authors.forename: Oyebode
authors.initials: O
authors.lastname: Olakanmi
authors.forename: Karlyn
authors.initials: K
authors.lastname: Beer
authors.forename: Geoffrey
authors.initials: G
authors.lastname: McKay
authors.forename: Richard
authors.initials: R
authors.lastname: Siehnel
authors.forename: James
authors.initials: J
authors.lastname: Schafhauser
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Britigan
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Singh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002374:Catalase / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004361:Drug Tolerance; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D005260:Female; D017665:Hydroxyl Radical / Q000378:metabolism; D006912:Hydroxyquinolines / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D015242:Ofloxacin / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D012694:Serine / Q000031:analogs & derivatives / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D006912:Hydroxyquinolines; C028002:serine hydroxamate; D017665:Hydroxyl Radical; D012694:Serine; D015242:Ofloxacin; D002374:Catalase; D013482:Superoxide Dismutase
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