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Whole cell screen for inhibitors of pH homeostasis in Mycobacterium tuberculosis.

TitleWhole cell screen for inhibitors of pH homeostasis in Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2013
AuthorsDarby CM, Ingólfsson HI, Jiang X, Shen C, Sun M, Zhao N, Burns K, Liu G, Ehrt S, J Warren D, Andersen OS, Anderson OS, Brickner SJ, Nathan C
JournalPLoS One
Volume8
Issue7
Paginatione68942
Date Published2013
ISSN1932-6203
KeywordsAcid-Base Equilibrium, Animals, Antitubercular Agents, Cell Line, High-Throughput Screening Assays, Homeostasis, Humans, Hydrogen-Ion Concentration, Membrane Potentials, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Vero Cells
Abstract

Bacterial pathogens like Mycobacterium tuberculosis (Mtb) encounter acidic microenvironments in the host and must maintain their acid-base homeostasis to survive. A genetic screen identified two Mtb strains that cannot control intrabacterial pH (pHIB) in an acidic environment; infection with either strain led to severe attenuation in mice. To search for additional proteins that Mtb requires to survive at low pH, we introduced a whole-cell screen for compounds that disrupt pHIB, along with counter-screens that identify ionophores and membrane perturbors. Application of these methods to a natural product library identified four compounds of interest, one of which may inhibit novel pathway(s). This approach yields compounds that may lead to the identification of pathways that allow Mtb to survive in acidic environments, a setting in which Mtb is resistant to most of the drugs currently used to treat tuberculosis.

DOI10.1371/journal.pone.0068942
Alternate JournalPLoS One
PubMed ID23935911
PubMed Central IDPMC3728290
Grant ListR01 GM021342 / GM / NIGMS NIH HHS / United States
AI081725 / AI / NIAID NIH HHS / United States

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