Molecular mechanisms of cell wall lipid transport in Mycobacterium tuberculosis

Presently, Tuberculosis (Tb), caused by Mycobacterium tuberculosis (Mtb), remains a global health threat, particularly with the emergence of drug-resistant strains and HIV and Tb co-infection that challenges the current Tb treatment. Preventative measures and several anti-Tb drugs target the lipids of the mycobacterial outer membrane consisting of mycolic acids amongst an array of glycolipids. In Mtb, there are thirteen outer membrane lipid transporters designated mycobacterial membrane protein large (MmpL) proteins. These proteins are also involved in heme acquisition and possibly drug resistance and nitrosative stress adaptation, contributing to mycobacterial survival and pathogenesis. MmpL proteins are structurally and phylogenetically classed as resistance-nodulation-division (RND) transporters that use protonmotive force (PMF) to mediate substrate translocation. Unlike their RND counterparts in Gram-negative bacteria the structure and mechanisms of these transporters in Mycobacteria are yet to be determined. This work aimed to investigate the mechanism of three transport systems: MmpL3, MmpL7 and DrrABC (encoded by mmpL3, mmpL7 and drrABC genes) using molecular modelling, genetics and lipid and protein ... (continues)