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J. Bacteriol. doi:10.1128/JB.00932-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Acid-susceptible mutants of Mycobacterium tuberculosis share hypersusceptibility to cell wall and oxidative stress and to the host environment

Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065

^* To whom correspondence should be addressed. Email: sae2004{at}med.cornell.edu.

	Abstract

Mycobacterium tuberculosis (Mtb) can persist in macrophage phagosomes that acidify to a pH of 4.5 after activation of the macrophage with IFN-. How the bacterium resists the low pH of the acidified phagosome is incompletely understood. A screen of 10,100 Mtb transposon mutants for mutants hypersensitive to pH 4.5 led to the discovery of 21 genes whose disruption attenuated survival of Mtb at low pH (41). Here we show that acid-sensitive Mtb mutants with transposon insertions in Rv2136c, Rv2224c, ponA2 and lysX were hypersensitive to antibiotics, SDS, heat shock and reactive oxygen and nitrogen intermediates, indicating that acid resistance can be associated with protection against other forms of stress. The Rv2136c mutant was impaired in intrabacterial pH homeostasis and unable to maintain a neutral intrabacterial pH in activated macrophages. The Rv2136c, Rv2224c and ponA2 mutants were attenuated in mice, with the Rv2136c mutant displaying the most severe level of attenuation. Pathways utilized by Mtb for acid resistance and intrabacterial pH maintenance are potential targets for chemotherapy.