Antimicrobial treatment improves mycobacterial survival in nonpermissive growth conditions

Abstract

PMCID: PMC3993263 Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.02774-13. ; Antimicrobials targeting cell wall biosynthesis are generally considered inactive against nonreplicating bacteria. Paradoxically, we found that under nonpermissive growth conditions, exposure of Mycobacterium bovis BCG bacilli to such antimicrobials enhanced their survival. We identified a transcriptional regulator, RaaS (for regulator of antimicrobial-assisted survival), encoded by bcg1279 (rv1219c) as being responsible for the observed phenomenon. Induction of this transcriptional regulator resulted in reduced expression of specific ATP-dependent efflux pumps and promoted long-term survival of mycobacteria, while its deletion accelerated bacterial death under nonpermissive growth conditions in vitro and during macrophage or mouse infection. These findings have implications for the design of antimicrobial drug combination therapies for persistent infectious diseases, such as tuberculosis. ; The study was supported by the Wellcome Trust (GM 081396/Z/06/Z, WT097828MF); BBSRC (O.T., D.I.Y., and M.Y.; P15165); European Union "New Medicines for TB—NM4TB" (LSHP-CT-2005-018923); Ministerio de Educación y Ciencia, Spain (G.T.; 2005/0565); the Schlumberger Foundation (A.S.); and the French Infrastructure for Integrated Structural Biology (M.C.G.; ANR-10-INSB-05-01). ; Peer-reviewed ; Publisher Version