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

TitleAcid-susceptible mutants of Mycobacterium tuberculosis share hypersusceptibility to cell wall and oxidative stress and to the host environment.
Publication TypeJournal Article
Year of Publication2009
AuthorsVandal OH, Roberts JA, Odaira T, Schnappinger D, Nathan CF, Ehrt S
JournalJ Bacteriol
Volume191
Issue2
Pagination625-31
Date Published2009 Jan
ISSN1098-5530
KeywordsAcids, Animals, Anti-Bacterial Agents, Cell Wall, Cells, Cultured, Female, Host-Pathogen Interactions, Humans, Hydrogen-Ion Concentration, Macrophages, Mice, Mice, Inbred C57BL, Microbial Sensitivity Tests, Mutagenesis, Insertional, Mutation, Mycobacterium tuberculosis, Oxidative Stress, Tuberculosis
Abstract

Mycobacterium tuberculosis can persist in macrophage phagosomes that acidify to a pH of approximately 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 M. tuberculosis transposon mutants for mutants hypersensitive to pH 4.5 led to the discovery of 21 genes whose disruption attenuated survival of M. tuberculosis at a low pH (41). Here, we show that acid-sensitive M. tuberculosis mutants with transposon insertions in Rv2136c, Rv2224c, ponA2, and lysX 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 ponA2 mutants were attenuated in mice, with the Rv2136c mutant displaying the most severe level of attenuation. Pathways utilized by M. tuberculosis for acid resistance and intrabacterial pH maintenance are potential targets for chemotherapy.

DOI10.1128/JB.00932-08
Alternate JournalJ Bacteriol
PubMed ID19011036
PubMed Central IDPMC2620805
Grant ListP01 AI056293 / AI / NIAID NIH HHS / United States

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