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ACS Chem Biol DOI:10.1021/cb4004817

Identification of novel inhibitors of nonreplicating Mycobacterium tuberculosis using a carbon starvation model.

Publication TypeJournal Article
Year of Publication2013
AuthorsGrant, SSchmidt, Kawate, T, Nag, PP, Silvis, MR, Gordon, K, Stanley, SA, Kazyanskaya, E, Nietupski, R, Golas, A, Fitzgerald, M, Cho, S, Franzblau, SG, Hung, DT
JournalACS Chem Biol
Date Published2013 Oct 18
KeywordsAntitubercular Agents, Carbon, Cell Cycle, Food, Microbial Sensitivity Tests, Models, Biological, Molecular Structure, Mycobacterium tuberculosis, Small Molecule Libraries

During Mycobacterium tuberculosis infection, a population of bacteria is thought to exist in a nonreplicating state, refractory to antibiotics, which may contribute to the need for prolonged antibiotic therapy. The identification of inhibitors of the nonreplicating state provides tools that can be used to probe this hypothesis and the physiology of this state. The development of such inhibitors also has the potential to shorten the duration of antibiotic therapy required. Here we describe the development of a novel nonreplicating assay amenable to high-throughput chemical screening coupled with secondary assays that use carbon starvation as the in vitro model. Together these assays identify compounds with activity against replicating and nonreplicating M. tuberculosis as well as compounds that inhibit the transition from nonreplicating to replicating stages of growth. Using these assays we successfully screened over 300,000 compounds and identified 786 inhibitors of nonreplicating M. tuberculosis In order to understand the relationship among different nonreplicating models, we tested 52 of these molecules in a hypoxia model, and four different chemical scaffolds in a stochastic persister model, and a streptomycin-dependent model. We found that compounds display varying levels of activity in different models for the nonreplicating state, suggesting important differences in bacterial physiology between models. Therefore, chemical tools identified in this assay may be useful for determining the relevance of different nonreplicating in vitro models to in vivo M. tuberculosis infection. Given our current limited understanding, molecules that are active across multiple models may represent more promising candidates for further development.


Alternate JournalACS Chem. Biol.
PubMed ID23898841
PubMed Central IDPMC3864639
Grant ListK08 AI085033 / AI / NIAID NIH HHS / United States
R03 MH087444 / MH / NIMH NIH HHS / United States
K08AI085033 / AI / NIAID NIH HHS / United States
R03MH087444 / MH / NIMH NIH HHS / United States