title: Acid-susceptible mutants of Mycobacterium tuberculosis share hypersusceptibility to cell wall and oxidative stress and to the host environment.
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.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Omar H
authors.initials: OH
authors.lastname: Vandal
authors.forename: Julia A
authors.initials: JA
authors.lastname: Roberts
authors.forename: Toshiko
authors.initials: T
authors.lastname: Odaira
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnappinger
authors.forename: Carl F
authors.initials: CF
authors.lastname: Nathan
authors.forename: Sabine
authors.initials: S
authors.lastname: Ehrt
mesh_terms: D000143:Acids / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002473:Cell Wall / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D016254:Mutagenesis, Insertional; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D014376:Tuberculosis / Q000382:microbiology*
chemical_list: D000143:Acids; D000900:Anti-Bacterial Agents