Document Detail


Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening.
MedLine Citation:
PMID:  22577943     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Sarah A Stanley; Sarah Schmidt Grant; Tomohiko Kawate; Noriaki Iwase; Motohisa Shimizu; Carl Wivagg; Melanie Silvis; Edward Kazyanskaya; John Aquadro; Aaron Golas; Michael Fitzgerald; Huanqin Dai; Lixin Zhang; Deborah T Hung
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-21
Journal Detail:
Title:  ACS chemical biology     Volume:  7     ISSN:  1554-8937     ISO Abbreviation:  ACS Chem. Biol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2012-11-21     Revised Date:  2013-08-20    
Medline Journal Info:
Nlm Unique ID:  101282906     Medline TA:  ACS Chem Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1377-84     Citation Subset:  IM    
Affiliation:
The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
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MeSH Terms
Descriptor/Qualifier:
Antitubercular Agents / chemistry,  pharmacology*
Biochemistry / methods
Cell Wall / metabolism
Chemistry, Pharmaceutical / methods
Dose-Response Relationship, Drug
Drug Design
Drug Discovery
Drug Evaluation, Preclinical / methods
Glycerol / chemistry
Green Fluorescent Proteins / metabolism
Microbial Sensitivity Tests
Models, Chemical
Mutation
Mycobacterium tuberculosis / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
K08 AI085033/AI/NIAID NIH HHS; K08AI085033/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antitubercular Agents; 147336-22-9/Green Fluorescent Proteins; 56-81-5/Glycerol
Comments/Corrections

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