Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street Southeast, Minneapolis, MN, 55455, USA.
Mycobacteria Research Laboratories, Microbiology, Immunology, and Pathology Department, Colorado State University, Fort Collins, CO, 80523, USA.
Eur J Med Chem. 2023 Mar 5;249:115125. doi: 10.1016/j.ejmech.2023.115125. Epub 2023 Jan 18.
The electron transport chain (ETC) in the cell membrane consists of a series of redox complexes that transfer electrons from electron donors to acceptors and couples this electron transfer with the transfer of protons (H) across a membrane. This process generates proton motive force which is used to produce ATP and a myriad of other functions and is essential for the long-term survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), under the hypoxic conditions present within infected granulomas. Menaquinone (MK), an important carrier molecule within the mycobacterial ETC, is synthesized de novo by a cluster of enzymes known as the classic/canonical MK biosynthetic pathway. MenA (1,4-dihydroxy-2-naphthoate prenyltransferase), the antepenultimate enzyme in this pathway, is a verified target for TB therapy. In this study, we explored structure-activity relationships of a previously discovered MenA inhibitor scaffold, seeking to improve potency and drug disposition properties. Focusing our campaign upon three molecular regions, we identified two novel inhibitors with potent activity against MenA and Mtb (IC = 13-22 μM, GIC = 8-10 μM). These analogs also displayed substantially improved pharmacokinetic parameters and potent synergy with other ETC-targeting agents, achieving nearly complete sterilization of Mtb in combination therapy within two weeks in vivo. These new inhibitors of MK biosynthesis present a promising new strategy to curb the continued spread of TB.
细胞膜中的电子传递链（ETC）由一系列氧化还原复合物组成，这些复合物将电子从电子供体转移到受体，并将这种电子转移与质子（H）在膜上的转移相耦合。这个过程产生质子动力势，用于产生 ATP 和许多其他功能，对于在感染性肉芽肿内存在的缺氧条件下长期存活的结核分枝杆菌（Mtb），即结核病（TB）的病原体，是必不可少的。menaquinone（MK）是细菌 ETC 中的一种重要载体分子，由一组称为经典/规范 MK 生物合成途径的酶从头合成。MenA（1,4-二羟基-2-萘酸 prenyltransferase）是该途径中的倒数第二酶，是结核病治疗的验证靶点。在这项研究中，我们探索了先前发现的 MenA 抑制剂支架的结构-活性关系，旨在提高其效力和药物处置特性。我们将研究重点放在三个分子区域上，确定了两种具有针对 MenA 和 Mtb 的强大活性的新型抑制剂（IC=13-22μM，GIC=8-10μM）。这些类似物还显示出显著改善的药代动力学参数和与其他 ETC 靶向剂的强大协同作用，在体内联合治疗中，在两周内几乎完全消除了 Mtb 的感染。这些新的 MK 生物合成抑制剂为遏制结核病的持续传播提供了一种有前途的新策略。
