Description:
<jats:title>ABSTRACT</jats:title><jats:p><jats:italic>Mycobacterium tuberculosis</jats:italic>can persist in macrophage phagosomes that acidify to a pH of ∼4.5 after activation of the macrophage with gamma interferon. How the bacterium resists the low pH of the acidified phagosome is incompletely understood. A screen of 10,100<jats:italic>M. tuberculosis</jats:italic>transposon mutants for mutants hypersensitive to pH 4.5 led to the discovery of 21 genes whose disruption attenuated survival of<jats:italic>M. tuberculosis</jats:italic>at a low pH (41). Here, we show that acid-sensitive<jats:italic>M. tuberculosis</jats:italic>mutants with transposon insertions in Rv2136c, Rv2224c,<jats:italic>ponA2</jats:italic>, and<jats:italic>lysX</jats:italic>were hypersensitive to antibiotics, sodium dodecyl sulfate, 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<jats:italic>ponA2</jats:italic>mutants were attenuated in mice, with the Rv2136c mutant displaying the most severe level of attenuation. Pathways utilized by<jats:italic>M. tuberculosis</jats:italic>for acid resistance and intrabacterial pH maintenance are potential targets for chemotherapy.</jats:p>