Active Starvation Responses Mediate Antibiotic Tolerance in Biofilms and Nutrient-Limited Bacteria

• Published in: Science (American Association for the Advancement of Science) 2011-11, Vol.334 (6058), p.982-986
• Main Authors: Nguyen, Dao, Joshi-Datar, Amruta, Lepine, Francois, Bauerle, Elizabeth, Olakanmi, Oyebode, Beer, Karlyn, McKay, Geoffrey, Siehnel, Richard, Schafhauser, James, Wang, Yun, Britigan, Bradley E., Singh, Pradeep K.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotic tolerance; Antibiotics; Antibiotics (antibacterial agents, antifungal agents); Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents; Applied microbiology; Bacteria; Bacteriology; Biofilms; Biofilms - drug effects; Biofilms - growth & development; Biological and medical sciences; Biotechnology; Catalase; Catalase - metabolism; Cell death; Cell growth; Computer Science; DNA; Drug Resistance, Bacterial; Drug Tolerance; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli - growth & development; Escherichia coli - physiology; Female; Fundamental and applied biological sciences. Psychology; Hydroxyl Radical; Hydroxyl Radical - metabolism; Hydroxyquinolines; Hydroxyquinolines - metabolism; Infections; Life Sciences; Mice; Mice, Inbred C57BL; Microbiology; Microbiology and Parasitology; Mutation; Nutrients; Ofloxacin; Ofloxacin - pharmacology; Ofloxacin - therapeutic use; Overproduction; Oxidative Stress; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - growth & development; Pseudomonas aeruginosa - physiology; Pseudomonas Infections; Pseudomonas Infections - drug therapy; Pseudomonas Infections - microbiology; Serine; Serine - analogs & derivatives; Serine - pharmacology; Starvation; Superoxide Dismutase; Superoxide Dismutase - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1211037

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.