Intricate link between siderophore secretion and drug efflux in Mycobacterium tuberculosis.
Intricate link between siderophore secretion and drug efflux in Mycobacterium tuberculosis.
复制标题
结核分枝杆菌铁载体分泌与药物流出之间的复杂联系。
DOI：
10.1128/aac.01629-22
复制
发表时间：
2023
影响因子：
4.9
通讯作者：
Niederweis,Michael
中科院分区：
文献类型：
--
作者：
Meikle,Virginia;Zhang,Lei;Niederweis,Michael
耐药性结核分枝杆菌是一个世界性的卫生保健问题，使目前的结核病（TB）药物无效。药物外排是细菌耐药的重要机制。MmpL 4和MmpL 5转运蛋白与其相关的MmpS 4和MmpS 5蛋白形成功能冗余的复合物，并构成了M的基本铁载体分泌系统的内膜组分。结核失活铁载体分泌对M.结核病是由于在低铁条件下的自我中毒，并导致小鼠的强毒力缺陷。在这项研究中，我们表明，M.缺乏MmpS 4-MmpL 4和MmpS 5-MmpL 5系统的组分的结核病患者对贝达喹啉、氯法齐明和利福必特更敏感，贝达喹啉、氯法齐明和利福必特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类似的功能的MmpL 4和MmpL 5转运铁载体和药物分泌，互补实验表明，MmpS 4-MmpL 4蛋白单独不足以恢复药物流出anM。与MmpS 5-MmpL 5相反，缺乏两个操纵子的结核病突变体。重要的是，M。缺乏最近发现的周质Rv 0455 c蛋白（其也是铁载体分泌所必需的）的结核病患者对相同的药物更敏感。这些结果揭示了一个有希望的目标，为发展双功能结核病药物，这可能毒害M。通过阻断铁载体的分泌，与其他药物协同作用，削弱药物外排。
Drug-resistantMycobacterium tuberculosisis 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 ofM. tuberculosis. Inactivating siderophore secretion is toxic forM. tuberculosisdue to self-poisoning at low-iron conditions and leads to a strong virulence defect in mice. In this study, we show thatM. tuberculosismutants 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 anM. tuberculosismutant lacking both operons, in contrast to MmpS5-MmpL5. Importantly, anM. tuberculosismutant 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 poisonM. tuberculosisby blocking siderophore secretion and synergize with other drugs by impairing drug efflux.