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ACS Chem Biol DOI:10.1021/cb300151m

Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening.

Publication TypeJournal Article
Year of Publication2012
AuthorsStanley, SA, Grant, SSchmidt, Kawate, T, Iwase, N, Shimizu, M, Wivagg, C, Silvis, M, Kazyanskaya, E, Aquadro, J, Golas, A, Fitzgerald, M, Dai, H, Zhang, L, Hung, DT
JournalACS Chem Biol
Volume7
Issue8
Pages1377-84
Date Published2012 Aug 17
ISSN1554-8937
KeywordsAntitubercular Agents, Biochemistry, Cell Wall, Chemistry, Pharmaceutical, Dose-Response Relationship, Drug, Drug Design, Drug Discovery, Drug Evaluation, Preclinical, Glycerol, Green Fluorescent Proteins, Microbial Sensitivity Tests, Models, Chemical, Mutation, Mycobacterium tuberculosis
Abstract

Despite the urgent need for new antitubercular drugs, few are on the horizon. To combat the problem of emerging drug resistance, structurally unique chemical entities that inhibit new targets will be required. Here we describe our investigations using whole cell screening of a diverse collection of small molecules as a methodology for identifying novel inhibitors that target new pathways for Mycobacterium tuberculosis drug discovery. We find that conducting primary screens using model mycobacterial species may limit the potential for identifying new inhibitors with efficacy against M. tuberculosis. In addition, we confirm the importance of developing in vitro assay conditions that are reflective of in vivo biology for maximizing the proportion of hits from whole cell screening that are likely to have activity in vivo. Finally, we describe the identification and characterization of two novel inhibitors that target steps in M. tuberculosis cell wall biosynthesis. The first is a novel benzimidazole that targets mycobacterial membrane protein large 3 (MmpL3), a proposed transporter for cell wall mycolic acids. The second is a nitro-triazole that inhibits decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1), an epimerase required for cell wall biosynthesis. These proteins are both among the small number of new targets that have been identified by forward chemical genetics using resistance generation coupled with genome sequencing. This suggests that methodologies currently employed for screening and target identification may lead to a bias in target discovery and that alternative methods should be explored.

URLhttp://dx.doi.org/10.1021/cb300151m
DOI10.1021/cb300151m
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22577943?dopt=Abstract

Alternate JournalACS Chem. Biol.
PubMed ID22577943
PubMed Central IDPMC3560293
Grant ListK08 AI085033 / AI / NIAID NIH HHS / United States
K08AI085033 / AI / NIAID NIH HHS / United States