4bae
From Proteopedia
Optimisation of pyrroleamides as mycobacterial GyrB ATPase inhibitors: Structure Activity Relationship and in vivo efficacy in the mouse model of tuberculosis
Structural highlights
FunctionGYRB_MYCSM DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings. Publication Abstract from PubMedMoxifloxacin has shown excellent activity against drug sensitive as well as drug resistant tuberculosis (TB) thus confirming DNA gyrase as a clinically validated target for discovering novel anti-TB agents. We have identified novel inhibitors in the pyrrolamide class which kill Mycobacterium tuberculosis through inhibition of ATPase activity catalysed by the GyrB domain of DNA gyrase. A homology model of M.tuberculosis H37Rv GyrB domain was used for deciphering structure activity relationship and binding interactions of inhibitors with mycobacterial GyrB enzyme. Proposed binding interactions were later confirmed through co-crystal structure studies with Mycobacterium smegmatis GyrB ATPase domain. The most potent compound in this series inhibited supercoiling activity of DNA gyrase with an IC50 < 5 nM, an MIC of 0.03 mug/mL against M.tuberculosis H37Rv and an MIC90 < 0.25 mug/mL against 99 drug resistant, clinical isolates of M.tuberculosis. The frequency of isolating spontaneous resistant mutants was approximately 10-6 to 10-8 and the point mutation mapped to M.tuberculosis GyrB domain (Ser 208 Ala) thus confirming its mode of action. The best compound tested for in vivo efficacy in the mouse model showed 1.1 log reduction in lung CFU in the acute model and 0.7 log reduction in the chronic model. This class of GyrB inhibitors could be developed as novel anti-TB agents. Optimization of pyrrolamides as mycobacterial GyrB ATPase inhibitors: Structure Activity Relationship and in vivo efficacy in the mouse model of tuberculosis.,Hameed SP, Solapure S, Mukherjee K, Nandi V, Waterson D, Shandil R, Balganesh M, Sambandamurthy VK, Raichurkar AK, Deshpande A, Ghosh A, Awasthy D, Shanbhag G, Sheikh G, McMiken H, Puttur J, Reddy J, Werngren J, Read J, Kumar M, R M, Chinnapattu M, Madhavapeddi P, Manjrekar P, Basu R, Gaonkar S, Sharma S, Hoffner S, Humnabadkar V, Subbulakshmi V, Panduga V Antimicrob Agents Chemother. 2013 Oct 14. PMID:24126580[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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