Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi 835215, India.
Mycobacteria Research Laboratory, School of Natural Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
Molecules. 2023 Dec 15;28(24):8115. doi: 10.3390/molecules28248115.
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., . Molecular docking, dynamics, and MMPBSA calculations enabled us to comprehend 's stable binding at the active site pocket of and the results imply that the 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 against in infected macrophages is noted in comparison to moderate in vitro antimycobacterial efficacy (64 μg/mL) against . also demonstrates whole-cell efflux pump inhibitory activity against . Identification of by focusing on the modular domain paves the way for accelerating novel anti-TB antibiotic discoveries.
耐药结核病（DR-TB）临床病例的失控传播需要紧急发现具有新型作用机制的新型化学型。在这里，我们报告了通过针对苯并恶唑啉合酶（MbtB）的环化（Cy）结构域，合理设计的新型过渡态类似物（TSA）的化学合成，MbtB 是条件必需的铁载体生物合成途径的关键酶。在缺铁和富铁培养基中进行生物测定指导的 TSA 类似物的评估，以了解针对一系列致病性和非致病性分枝杆菌菌株的靶标偏好性之后，我们确定了一个命中物，即 。分子对接、动力学和 MMPBSA 计算使我们能够理解 在 和结果表明， 结合口袋对吸电子官能团具有很强的亲和力，并有助于酶和配体之间的稳定极性相互作用。此外，与体外对 的中度抗分枝杆菌功效（64 μg/mL）相比， 在感染的巨噬细胞中对 的细胞内杀伤功效（8 μg/mL）得到增强。 还显示出针对整个细胞外排泵的抑制活性。通过关注模块化 结构域来鉴定 ，为加速新型抗结核抗生素的发现铺平了道路。
