Rationally designed novel Phenyloxazoline Synthase Inhibitors: chemical synthesis and biological evaluation to accelerate the discovery of new antimycobacterial antibiotics
Shyam, M. and Bhattacharje, G. and Daniel, C. and Kumar, A. and Yadav, P. and Mukherjee, P. and Singh, S. and Das, A.K. and Narender, T. and Singh, A. and Jayaprakash, V. and Bhakta, Sanjib (2023) Rationally designed novel Phenyloxazoline Synthase Inhibitors: chemical synthesis and biological evaluation to accelerate the discovery of new antimycobacterial antibiotics. Molecules 28 (24), p. 8115. ISSN 1420-3049.
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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 MbtB_Cy and the results imply that the MbtB_Cy 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 MbtB_Cy domain paves the way for accelerating novel anti-TB antibiotic discoveries.
Metadata
| Item Type: | Article |
|---|---|
| Keyword(s) / Subject(s): | mycobactin metabolism, phenyloxazoline synthase, cyclization domain, transition-state analogues, MD simulations, MMPBSA studies, intracellular killing, efflux pump |
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Depositing User: | Chris Daniel |
| Date Deposited: | 22 Apr 2024 13:16 |
| Last Modified: | 23 Apr 2024 07:15 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/53415 |
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