流出
结核分枝杆菌
肺结核
铁载体
微生物学
生物
氯法齐明
毒力
ATP结合盒运输机
基岩
分泌物
抗药性
运输机
医学
细菌
生物化学
免疫学
遗传学
基因
麻风病
病理
作者
Virginia Meikle,Lei Zhang,Michael Niederweis
摘要
Drug-resistant Mycobacterium tuberculosis 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 M. tuberculosis. Inactivating siderophore secretion is toxic for M. tuberculosis due to self-poisoning at low-iron conditions and leads to a strong virulence defect in mice. In this study, we show that M. tuberculosis 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 M. tuberculosis mutant lacking both operons, in contrast to MmpS5-MmpL5. Importantly, an M. tuberculosis 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 M. tuberculosis by blocking siderophore secretion and synergize with other drugs by impairing drug efflux.
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