Identification of diphenyl furan derivatives via high throughput and computational studies as ArgA inhibitors of Mycobacterium tuberculosis.

Autor: Khurana H; Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India., Srivastava M; Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India., Chaudhary D; Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India; Manipal academy of higher education, Manipal, Karnataka 576104. India., Gosain TP; Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India., Kumari R; Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India., Bean AC; Department of Chemistry and Physics, Augusta University, 2500 Walton Way, Augusta, GA 30904, USA., Chugh S; Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India., Maiti TK; Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India., Stephens CE; Department of Chemistry and Physics, Augusta University, 2500 Walton Way, Augusta, GA 30904, USA. Electronic address: CSTEPHE7@augusta.edu., Asthana S; Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India. Electronic address: sasthana@thsti.res.in., Singh R; Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India. Electronic address: ramandeep@thsti.res.in.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2021 Dec 15; Vol. 193 (Pt B), pp. 1845-1858. Date of Electronic Publication: 2021 Nov 08.
DOI: 10.1016/j.ijbiomac.2021.11.017
Abstrakt: Microbial amino acid biosynthetic pathways are underexploited for the development of anti-bacterial agents. N-acetyl glutamate synthase (ArgA) catalyses the first committed step in L-arginine biosynthesis and is essential for M. tuberculosis growth. Here, we have purified and optimized assay conditions for the acetylation of l-glutamine by ArgA. Using the optimized conditions, high throughput screening was performed to identify ArgA inhibitors. We identified 2,5-Bis (2-chloro-4-guanidinophenyl) furan, a dicationic diaryl furan derivatives, as ArgA inhibitor, with a MIC 99 values of 1.56 μM against M. tuberculosis. The diaryl furan derivative displayed bactericidal killing against both M. bovis BCG and M. tuberculosis. Inhibition of ArgA by the lead compound resulted in transcriptional reprogramming and accumulation of reactive oxygen species. The lead compound and its derivatives showed micromolar binding with ArgA as observed in surface plasmon resonance and tryptophan quenching experiments. Computational and dynamic analysis revealed that these scaffolds share similar binding site residues with L-arginine, however, with slight variations in their interaction pattern. Partial restoration of growth upon supplementation of liquid cultures with either L-arginine or N-acetyl cysteine suggests a multi-target killing mechanism for the lead compound. Taken together, we have identified small molecule inhibitors against ArgA enzyme from M. tuberculosis.
(Copyright © 2021. Published by Elsevier B.V.)
Databáze: MEDLINE
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