4BAE

Optimisation of pyrroleamides as mycobacterial GyrB ATPase inhibitors: Structure Activity Relationship and in vivo efficacy in the mouse model of tuberculosis

Summary for 4BAE

• Entry DOI: 10.2210/pdb4bae/pdb
• Related: 4B6C
• Descriptor: DNA GYRASE SUBUNIT B, CALCIUM ION, 2-[(3S,4R)-4-[(3-bromanyl-4-chloranyl-5-methyl-1H-pyrrol-2-yl)carbonylamino]-3-methoxy-piperidin-1-yl]-4-(2-methyl-1,2,4-triazol-3-yl)-1,3-thiazole-5-carboxylic acid, ... (5 entities in total)
• Functional Keywords: isomerase, dna topoisomerase, inhibitor
• Biological source: MYCOBACTERIUM SMEGMATIS
• Cellular location: Cytoplasm : P0C559
• Total number of polymer chains: 4
• Total formula weight: 93882.17

Authors

Read, J.A.,Gingell, H.G.,Madhavapeddi, P. (deposition date: 2012-09-13, release date: 2013-10-30, Last modification date: 2023-12-20)

Primary citation

Hameed, S.P.,Solapure, S.,Mukherjee, K.,Nandi, V.,Waterson, D.,Shandil, R.,Balganesh, M.,Sambandamurthy, V.K.,Raichurkar, A.K.,Deshpande, A.,Ghosh, A.,Awasthy, D.,Shanbhag, G.,Sheikh, G.,Mcmiken, H.,Puttur, J.,Reddy, J.,Werngren, J.,Read, J.,Kumar, M.,Manjunatha, R.,Chinnapattu, M.,Madhavapeddi, P.,Manjrekar, P.,Basu, R.,Gaonkar, S.,Sharma, S.,Hoffner, S.,Humnabadkar, V.,Subbulakshmi, V.,Panduga, V.
Optimization of Pyrrolamides as Mycobacterial Gyrb ATPase Inhibitors: Structure Activity Relationship and in Vivo Efficacy in the Mouse Model of Tuberculosis.
Antimicrob.Agents Chemother., 58:61-, 2014

PubMed Abstract: Moxifloxacin 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 catalyzed by the GyrB domain of DNA gyrase. A homology model of the M. tuberculosis H37Rv GyrB domain was used for deciphering the structure-activity relationship and binding interactions of inhibitors with mycobacterial GyrB enzyme. Proposed binding interactions were later confirmed through cocrystal structure studies with the Mycobacterium smegmatis GyrB ATPase domain. The most potent compound in this series inhibited supercoiling activity of DNA gyrase with a 50% inhibitory concentration (IC50) of <5 nM, an MIC of 0.03 μg/ml against M. tuberculosis H37Rv, and an MIC90 of <0.25 μg/ml against 99 drug-resistant clinical isolates of M. tuberculosis. The frequency of isolating spontaneous resistant mutants was ∼10(-6) to 10(-8), and the point mutation mapped to the M. tuberculosis GyrB domain (Ser208 Ala), thus confirming its mode of action. The best compound tested for in vivo efficacy in the mouse model showed a 1.1-log reduction in lung CFU in the acute model and a 0.7-log reduction in the chronic model. This class of GyrB inhibitors could be developed as novel anti-TB agents.

PubMed: 24126580
DOI: 10.1128/AAC.01751-13

Experimental method

X-RAY DIFFRACTION (2.35 Å)