Lipid transport in Mycobacterium tuberculosis and its implications in virulence and drug development

Tuberculosis is still a major health problem worldwide and one of the main causes of death by a single infectious agent. Only few drugs are really effective to treat tuberculosis, hence, the emergence of multiple, extensively, and totally drug resistant bacilli compromises the already difficult antituberculosis treatments. Given the persistent global burden of tuberculosis, it is crucial to understand the underlying mechanisms required for the pathogenicity of Mycobacterium tuberculosis (Mtb), the causal agent of tuberculosis, in order to pave the way for developing better drugs and strategies to treat and prevent tuberculosis. The exclusive mycobacterial cell wall lipids such as trehalose monomycolate and dimycolate (TMM, TDM), phthiocerol dimycocerosate (PDIM), sulpholipid-1 (SL-1), diacyl trehalose (DAT), and pentacyl trehalose (PAT), among others, are known to play an important role in pathogenesis; thus, proteins responsible for their transport are potential virulence factors. MmpL and MmpS proteins mediate transport of important cell wall lipids across the mycobacterial membrane. In Mtb, MmpL3, MmpL7 and MmpL8 transport TMM, PDIM and SL-1 respectively. The translocation of DAT and biosynthesis of PAT is likely due to MmpL10. MmpL and MmpS proteins are involved in other processes such as drug efflux (MmpL5 and MmpL7), siderophore export (MmpL4/MmpS4 and MmpL5/MmpS5), and heme uptake (MmpL3 and MmpL11). Altogether, these proteins can be regarded as new potential targets for antituberculosis drug development. We will review recent advances in developing inhibitors of MmpL proteins, in the challenging context of targeting membrane proteins and the future prospects for potential antituberculosis drug candidates.