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Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

DOI: 10.1073/pnas.1309171110 DOI Help
PMID: 23776209 PMID Help

Authors: Feng Wang (The Scripps Research Institute; California Institute for Biomedical Research) , Dhinakaran Sambandan (Albert Einstein College of Medicine,) , Rajkumar Halder , Jianing Wang (The Scripps Research Institute) , Sarah M. Batt (University of Birmingham) , Brian Weinrick (Albert Einstein College of Medicine) , Insha Ahmad (The Scripps Research Institute) , Pengyu Yang (The Scripps Research Institute) , Yong Zhang (The Scripps Research Institute) , John Kim (Albert Einstein College of Medicine) , Morad Hassani (Albert Einstein College of Medicine) , Stanislav Huszar (Comenius University) , Claudia Trefzer (Ecole Polytechnique Fédérale de Lausanne (EPFL)) , Zhenkun Ma (Global Alliance for Tuberculosis Drug Development) , Takushi Kaneko (Global Alliance for Tuberculosis Drug Development) , Khisi E. Mdluli (Global Alliance for Tuberculosis Drug Development) , Scott Franzblau (University of Illinois) , Arnab K. Chatterjee (bCalifornia Institute for Biomedical Research) , Kai Johnsson (Genomics Institute of the Novartis Research Foundation) , Katarina Mikusova (Comenius University,) , Gurdyal S. Besra (University of Birmingham) , Klaus Futterer (University of Birmingham) , Scott H. Robbins (MedImmune LLC) , S. Whitney Barnes (Genomics Institute of the Novartis Research Foundation) , John R. Walker (Genomics Institute of the Novartis Research Foundation) , William R. Jacobs (Albert Einstein College of Medicine) , Peter G. Schultz (California Institute for Biomedical Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 110 (27) , PAGES E2510 - E2517

State: Published (Approved)
Published: July 2013
Diamond Proposal Number(s): 6388

Abstract: A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-β-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents.

Journal Keywords: Amino; Animals; Antitubercular; Bacterial; Benzothiazoles; Biofilms; Carbohydrate; Drug; Bacterial; Female; Genes; Bacterial; High-Throughput; Isoniazid; Mice; Mice; Inbred; Microbial; Mycobacterium; Oxidoreductases; Rifampin; Thiophenes; Tuberculosis; Pulmonary

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I02-Macromolecular Crystallography