Shyam, M and Bhattacharje, G and Daniel, C and Kumar, A and Yadav, P and Mukherjee, P and Singh, S and Das, AK and Narender, T and Singh, A and Jayaprakash, V and Bhakta, S (2023) Rationally Designed Novel Phenyloxazoline Synthase Inhibitors: Chemical Synthesis and Biological Evaluation to Accelerate the Discovery of New Antimycobacterial Antibiotics. In: Molecules, 28 (24).
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Abstract
The uncontrolled spread of drug-resistant tuberculosis (DR-TB) clinical cases necessitates the urgent discovery of newer chemotypes with novel mechanisms of action. Here, we report the chemical synthesis of rationally designed novel transition-state analogues (TSAs) by targeting the cyclization (Cy) domain of phenyloxazoline synthase (MbtB), a key enzyme of the conditionally essential siderophore biosynthesis pathway. Following bio-assay-guided evaluation of TSA analogues preferentially in iron-deprived and iron-rich media to understand target preferentiality against a panel of pathogenic and non-pathogenic mycobacteria strains, we identified a hit, i.e., TSA-5. Molecular docking, dynamics, and MMPBSA calculations enabled us to comprehend TSA-5�s stable binding at the active site pocket of MbtBCy and the results imply that the MbtBCy binding pocket has a strong affinity for electron-withdrawing functional groups and contributes to stable polar interactions between enzyme and ligand. Furthermore, enhanced intracellular killing efficacy (8 μg/mL) of TSA-5 against Mycobacterium aurum in infected macrophages is noted in comparison to moderate in vitro antimycobacterial efficacy (64 μg/mL) against M. aurum. TSA-5 also demonstrates whole-cell efflux pump inhibitory activity against Mycobacterium smegmatis. Identification of TSA-5 by focusing on the modular MbtBCy domain paves the way for accelerating novel anti-TB antibiotic discoveries. © 2023 by the authors.
| Item Type: | Journal Article |
|---|---|
| Publication: | Molecules |
| Publisher: | Multidisciplinary Digital Publishing Institute (MDPI) |
| Additional Information: | The copyright for this article belongs to Multidisciplinary Digital Publishing Institute (MDPI). |
| Keywords: | antiinfective agent; iron; tuberculostatic agent, chemistry; metabolism; molecular docking; Mycobacterium smegmatis; Mycobacterium tuberculosis, Anti-Bacterial Agents; Antitubercular Agents; Iron; Molecular Docking Simulation; Mycobacterium smegmatis; Mycobacterium tuberculosis |
| Department/Centre: | Division of Biological Sciences > Microbiology & Cell Biology |
| Date Deposited: | 01 Mar 2024 08:04 |
| Last Modified: | 01 Mar 2024 08:04 |
| URI: | https://eprints.iisc.ac.in/id/eprint/84025 |
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