Targeting a bacterial stress response to enhance antibiotic action.
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.
Lee
Samuel
S
Departments of Genome Sciences and Medicine and Microbiology, University of Washington, Seattle, WA 98195, USA.
Hinz
Aaron
A
Bauerle
Elizabeth
E
Angermeyer
Angus
A
Juhaszova
Katy
K
Kaneko
Yukihiro
Y
Singh
Pradeep K
PK
Manoil
Colin
C
D000617:Aminoglycosides / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004251:DNA Transposable Elements / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D016254:Mutagenesis, Insertional; D009154:Mutation; D011552:Pseudomonas Infections / Q000382:microbiology / Q000517:prevention & control; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D014031:Tobramycin / Q000494:pharmacology*; D014774:Virulence / Q000187:drug effects
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004251:DNA Transposable Elements; D014031:Tobramycin
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