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

Harleen Khurana, Mitul Srivastava, Deepika Chaudhary, Tannu Priya Gosain, Raniki Kumari, Andrew C. Bean, Saurabh Chugh, Tushar Kanti Maiti, Chad E. Stephens, Shailendra Asthana, Ramandeep Singh

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1845-1858
Number of pages14
JournalInternational Journal of Biological Macromolecules
Volume193
DOIs
StatePublished - Dec 15 2021

Keywords

  • ArgA protein
  • Mycobacterium tuberculosis
  • Redox status
  • Small molecule inhibitors
  • Target-based screening

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Economics and Econometrics
  • Energy(all)

Fingerprint

Dive into the research topics of 'Identification of diphenyl furan derivatives via high throughput and computational studies as ArgA inhibitors of Mycobacterium tuberculosis'. Together they form a unique fingerprint.

Cite this