Khurana, Harleen and Srivastava, Mitul and Chaudhary, Deepika and Gosain, Tannu Priya and Kumari, Raniki and Bean, Andrew C. and Chugh, Saurabh and Maiti, Tushar Kanti and Stephens, Chad E. and Asthana, Shailendra and Singh, Ramandeep (2021) Identification of diphenyl furan derivative via high throughput and computational studies as ArgA inhibitor of Mycobacterium tuberculosis. International Journal of Biological Macromolecules. ISSN 01418130

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Abstract

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 MIC99 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.

Item Type:	Article
Subjects:	Biomedical Science Biochemical and Biophysical Sciences
Depositing User:	RCB Library
Date Deposited:	10 Jan 2022 07:11
Last Modified:	10 Jan 2022 07:11
URI:	http://rcb.sciencecentral.in/id/eprint/665

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