Identification of diphenyl furan derivatives via high throughput and computational studies as ArgA inhibitors of Mycobacterium tuberculosis
| Autor: | Mitul Srivastava, Tushar Kanti Maiti, Raniki Kumari, Tannu Priya Gosain, Ramandeep Singh, Harleen Khurana, Chad E. Stephens, Andrew C. Bean, Deepika Chaudhary, Shailendra Asthana, Saurabh Chugh |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
biology Tryptophan Amino-Acid N-Acetyltransferase Antitubercular Agents General Medicine Mycobacterium tuberculosis biology.organism_classification Biochemistry Small molecule Mycobacterium bovis Amino acid chemistry.chemical_compound Enzyme chemistry Biosynthesis Bacterial Proteins Structural Biology Binding site Enzyme Inhibitors Furans Molecular Biology Cysteine |
| Zdroj: | International journal of biological macromolecules. 193 |
| ISSN: | 1879-0003 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect