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Selective killing of nonreplicating mycobacteria.

TitleSelective killing of nonreplicating mycobacteria.
Publication TypeJournal Article
Year of Publication2008
AuthorsBryk R, Gold B, Venugopal A, Singh J, Samy R, Pupek K, Cao H, Popescu C, Gurney M, Hotha S, Cherian J, Rhee K, Ly L, Converse PJ, Ehrt S, Vandal O, Jiang X, Schneider J, Lin G, Nathan C
JournalCell Host Microbe
Volume3
Issue3
Pagination137-45
Date Published2008 Mar 13
ISSN1934-6069
KeywordsAcyltransferases, Animals, Antitubercular Agents, Bacterial Proteins, Cells, Cultured, Colony Count, Microbial, Enzyme Inhibitors, Gene Deletion, Genetic Complementation Test, Guinea Pigs, Hypoxia, Lung, Macrophages, Microbial Viability, Molecular Structure, Mycobacterium tuberculosis, Nitric Oxide, Rhodanine, Tuberculosis, Virulence, Virulence Factors
Abstract

Antibiotics are typically more effective against replicating rather than nonreplicating bacteria. However, a major need in global health is to eradicate persistent or nonreplicating subpopulations of bacteria such as Mycobacterium tuberculosis (Mtb). Hence, identifying chemical inhibitors that selectively kill bacteria that are not replicating is of practical importance. To address this, we screened for inhibitors of dihydrolipoamide acyltransferase (DlaT), an enzyme required by Mtb to cause tuberculosis in guinea pigs and used by the bacterium to resist nitric oxide-derived reactive nitrogen intermediates, a stress encountered in the host. Chemical screening for inhibitors of Mtb DlaT identified select rhodanines as compounds that almost exclusively kill nonreplicating mycobacteria in synergy with products of host immunity, such as nitric oxide and hypoxia, and are effective on bacteria within macrophages, a cellular reservoir for latent Mtb. Compounds that kill nonreplicating pathogens in cooperation with host immunity could complement the conventional chemotherapy of infectious disease.

DOI10.1016/j.chom.2008.02.003
Alternate JournalCell Host Microbe
PubMed ID18329613
PubMed Central IDPMC2423947
Grant ListN01-AI30036 / AI / NIAID NIH HHS / United States
UC1 AI062559-01 / AI / NIAID NIH HHS / United States
UC1 AI062559 / AI / NIAID NIH HHS / United States
N01AI30036 / AI / NIAID NIH HHS / United States
UC1-A1062559 / / PHS HHS / United States

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