Kumar Gautam, Kapoor Shobhna
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India; Departemnt of Natural Products, National Institute of Pharmaceutical Education and Research-Hyderabad, Hyderabad 500037, India.
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India; Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8528, Japan.
Bioorg Med Chem. 2023 Mar 1;81:117212. doi: 10.1016/j.bmc.2023.117212. Epub 2023 Feb 11.
Among the various bacterial infections, tuberculosis continues to hold center stage. Its causative agent, Mycobacterium tuberculosis, possesses robust defense mechanisms against most front-line antibiotic drugs and host responses due to their complex cell membranes with unique lipid molecules. It is now well-established that bacteria change their membrane composition to optimize their environment to survive and elude drug action. Thus targeting membrane or membrane components is a promising avenue for exploiting the chemical space focussed on developing novel membrane-centric anti-bacterial small molecules. These approaches are more effective, non-toxic, and can attenuate resistance phenotype. We present the relevance of targeting the mycobacterial membrane as a practical therapeutic approach. The review highlights the direct and indirect targeting of membrane structure and function. Direct membrane targeting agents cause perturbation in the membrane potential and can cause leakage of the cytoplasmic contents. In contrast, indirect membrane targeting agents disrupt the function of membrane-associated proteins involved in cell wall biosynthesis or energy production. We discuss the chronological chemical improvements in various scaffolds targeting specific membrane-associated protein targets, their clinical evaluation, and up-to-date account of their ''mechanisms of action, potency, selectivity'' and limitations. The sources of anti-TB drugs/inhibitors discussed in this work have emerged from target-based identification, cell-based phenotypic screening, drug repurposing, and natural products. We believe this review will inspire the exploration of uncharted chemical space for informing the development of new scaffolds that can inhibit novel mycobacterial membrane targets.
在各种细菌感染中，结核病仍然占据核心地位。其病原体结核分枝杆菌由于其具有独特脂质分子的复杂细胞膜，对大多数一线抗生素药物和宿主反应具有强大的防御机制。目前已经明确，细菌会改变其膜组成以优化其生存环境并逃避药物作用。因此，靶向细胞膜或膜成分是开发以膜为中心的新型抗菌小分子化学空间的一个有前景的途径。这些方法更有效、无毒，并且可以减弱耐药表型。我们阐述了靶向分枝杆菌膜作为一种实际治疗方法的相关性。该综述强调了对膜结构和功能的直接和间接靶向。直接膜靶向剂会扰乱膜电位并可能导致细胞质内容物泄漏。相比之下，间接膜靶向剂会破坏参与细胞壁生物合成或能量产生的膜相关蛋白的功能。我们讨论了针对特定膜相关蛋白靶点的各种支架的按时间顺序的化学改进、它们的临床评估以及它们的“作用机制、效力、选择性”和局限性的最新情况。本工作中讨论的抗结核药物/抑制剂来源包括基于靶点的鉴定、基于细胞的表型筛选、药物再利用和天然产物。我们相信这篇综述将激发对未知化学空间的探索，以推动能够抑制新型分枝杆菌膜靶点的新支架的开发。
