Department of Microbiology, University of Alabama at Birmingham , Birmingham, Alabama, USA.
Antimicrob Agents Chemother. 2023 Oct 18;67(10):e0162922. doi: 10.1128/aac.01629-22. Epub 2023 Sep 7.
Drug-resistant is a worldwide health-care problem rendering current tuberculosis (TB) drugs ineffective. Drug efflux is an important mechanism in bacterial drug resistance. The MmpL4 and MmpL5 transporters form functionally redundant complexes with their associated MmpS4 and MmpS5 proteins and constitute the inner membrane components of an essential siderophore secretion system of . Inactivating siderophore secretion is toxic for due to self-poisoning at low-iron conditions and leads to a strong virulence defect in mice. In this study, we show that mutants lacking components of the MmpS4-MmpL4 and MmpS5-MmpL5 systems are more susceptible to bedaquiline, clofazimine, and rifabutin, important drugs for treatment of drug-resistant TB. While genetic deletion experiments revealed similar functions of the MmpL4 and MmpL5 transporters in siderophore and drug secretion, complementation experiments indicated that the MmpS4-MmpL4 proteins alone are not sufficient to restore drug efflux in an mutant lacking both operons, in contrast to MmpS5-MmpL5. Importantly, an mutant lacking the recently discovered periplasmic Rv0455c protein, which is also essential for siderophore secretion, is more susceptible to the same drugs. These results reveal a promising target for the development of dual-function TB drugs, which might poison by blocking siderophore secretion and synergize with other drugs by impairing drug efflux.
耐药性是一个全球性的医疗保健问题，使当前的结核病（TB）药物失效。药物外排是细菌耐药性的一个重要机制。MmpL4 和 MmpL5 转运蛋白与它们相关的 MmpS4 和 MmpS5 蛋白形成功能冗余复合物，并构成必需的铁载体分泌系统的内膜成分。由于在低铁条件下的自我中毒，使铁载体分泌失活对 是有毒的，导致在小鼠中出现强烈的毒力缺陷。在这项研究中，我们表明缺乏 MmpS4-MmpL4 和 MmpS5-MmpL5 系统组件的 突变体对贝达喹啉、氯法齐明和利福布汀更敏感，这些药物是治疗耐药性结核病的重要药物。虽然遗传缺失实验揭示了 MmpL4 和 MmpL5 转运蛋白在铁载体和药物分泌中的相似功能，但互补实验表明，MmpS4-MmpL4 蛋白本身不足以在缺乏两个操纵子的 突变体中恢复药物外排，而 MmpS5-MmpL5 则可以。重要的是，缺乏最近发现的周质 Rv0455c 蛋白的 突变体对相同的药物也更敏感，该蛋白也是铁载体分泌所必需的。这些结果揭示了一种有前途的双重功能 TB 药物开发靶点，该靶点可能通过阻断铁载体分泌来毒害 ，并通过损害药物外排与其他药物协同作用。
