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

ACS Chemical Biology
Sarah Schmidt GrantDeborah T Hung

Abstract

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 mode...Continue Reading

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Related Concepts

Tuberculosis
Vitreous Carbon
Nutrients
Streptomycin
Cell Cycle
Mycobacterium tuberculosis H37Rv
Antitubercular Agents
Hypoxia
Small Molecule Libraries
Mycobacterium Tuberculosis, Susceptibility to Infection by

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