Intricate link between siderophore secretion and drug efflux in Mycobacterium tuberculosis

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.