Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Department of Chemistry, Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
Chemistry. 2023 May 22;29(29):e202203868. doi: 10.1002/chem.202203868. Epub 2023 Apr 12.
Mycobacterium tuberculosis (Mtb) was responsible for approximately 1.6 million deaths in 2021. With the emergence of extensive drug resistance, novel therapeutic agents are urgently needed, and continued drug discovery efforts required. Host-derived lipids such as cholesterol not only support Mtb growth, but are also suspected to function in immunomodulation, with links to persistence and immune evasion. Mtb cytochrome P450 (CYP) enzymes facilitate key steps in lipid catabolism and thus present potential targets for inhibition. Here we present a series of compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore which bind strongly to both Mtb cholesterol oxidases CYP125 and CYP142. Using a structure-guided approach, combined with biophysical characterization, compounds with micromolar range in-cell activity against clinically relevant drug-resistant isolates were obtained. These will incite further development of much-needed additional treatment options and provide routes to probe the role of CYP125 and CYP142 in Mtb pathogenesis.
结核分枝杆菌（Mtb）在 2021 年导致了约 160 万人死亡。随着广泛耐药性的出现，迫切需要新型治疗药物，并且需要继续进行药物发现工作。宿主来源的脂质，如胆固醇，不仅支持 Mtb 的生长，而且还可能在免疫调节中发挥作用，与持久性和免疫逃避有关。Mtb 细胞色素 P450（CYP）酶促进脂质分解代谢的关键步骤，因此是潜在的抑制靶标。在这里，我们提出了一系列基于乙基 5-(吡啶-4-基)-1H-吲哚-2-羧酸酯药效团的化合物，这些化合物与 Mtb 胆固醇氧化酶 CYP125 和 CYP142 结合紧密。通过结构导向方法，结合生物物理特性分析，获得了对具有临床相关性的耐药分离株具有微摩尔级在细胞活性的化合物。这些将进一步激发对急需的其他治疗选择的开发，并为研究 CYP125 和 CYP142 在 Mtb 发病机制中的作用提供途径。
