Targeting a bacterial stress response to enhance antibiotic action

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-08, Vol.106 (34), p.14570-14575
• Main Authors: Lee, Samuel, Hinz, Aaron, Bauerle, Elizabeth, Angermeyer, Angus, Juhaszova, Katy, Kaneko, Yukihiro, Singh, Pradeep K, Manoil, Colin
• Format: Article
• Language: English
• Subjects: Aminoglycosides; Aminoglycosides - pharmacology; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacteria; Biofilms; Biological Sciences; DNA Transposable Elements - genetics; Drug Resistance, Bacterial - genetics; Gene Expression Regulation, Bacterial; Genes, Bacterial - genetics; Genetic mutation; Infections; Libraries; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mutagenesis, Insertional; Mutation; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - pathogenicity; Pseudomonas Infections - microbiology; Pseudomonas Infections - prevention & control; Regulator genes; Rodents; Tobramycin - pharmacology; Transposons; Virulence - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0903619106

This report describes the identification and analysis of a 2-component regulator of Pseudomonas aeruginosa that is a potential aminoglycoside antibiotic combination therapy target. The regulator, AmgRS, was identified in a screen of a comprehensive, defined transposon mutant library for functions whose inactivation increased tobramycin sensitivity. AmgRS mutations enhanced aminoglycoside action against bacteria grown planktonically and in antibiotic tolerant biofilms, against genetically resistant clinical isolates, and in lethal infections of mice. Drugs targeting AmgRS would thus be expected to enhance the clinical efficacy of aminoglycosides. Unexpectedly, the loss of AmgRS reduced virulence in the absence of antibiotics, indicating that its inactivation could protect against infection directly as well as by enhancing aminoglycoside action. Transcription profiling and phenotypic analysis suggested that AmgRS controls an adaptive response to membrane stress, which can be caused by aminoglycoside-induced translational misreading. These results help validate AmgRS as a potential antibiotic combination target for P. aeruginosa and indicate that fundamental stress responses may be a valuable general source of such targets.