4kw5
M. tuberculosis DprE1 in complex with inhibitor TCA1
Structural highlights
Publication Abstract from PubMedA 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-beta-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. Identification of a small molecule with activity against drug-resistant and persistent tuberculosis.,Wang F, Sambandan D, Halder R, Wang J, Batt SM, Weinrick B, Ahmad I, Yang P, Zhang Y, Kim J, Hassani M, Huszar S, Trefzer C, Ma Z, Kaneko T, Mdluli KE, Franzblau S, Chatterjee AK, Johnson K, Mikusova K, Besra GS, Futterer K, Jacobs WR Jr, Schultz PG Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):E2510-7. doi:, 10.1073/pnas.1309171110. Epub 2013 Jun 17. PMID:23776209[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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