Despite the availability of antibiotics to combat Tuberculosis (TB), it is one of the leading causes of death due to infectious disease. Mtb is a successful pathogen because it survives within immune cells and effectively establishes and maintains a latent tuberculosis (TB) infection. Treatment of latent TB is lengthy in part because quiescent or slowly replicating Mtb acquires a drug-tolerant phenotype. Therefore, understanding the mechanisms underlying the establishment or maintenance of dormancy can inform new strategies for TB therapeutics. MmpL (Mycobacterial membrane protein large) transporters are dedicated to the transport of cell wall lipids. MmpL proteins are therefore crucia players in mycobacterial physiology and pathogenesis. MmpL3 is essential to mycobacterial viability; and MmpL4, MmpL5, MmpL7, MmpL8, MmpL10 and MmpL11 contribute to Mtb virulence. Our goal is to elucidate the function of MmpL11. Our data show that MmpL11 transported monomeromycolyl diacylglycerol and a mycolate ester wax to the M. smegmatis cell wall. These lipids belong to classes of lipid species that are sometimes referred to as storage lipids and are associated with dormant bacteria in vitro and accumulate in granulomas of TB patients. Therefore, it appears that MmpL11 plays a role in a clinically relevant, but poorly understood, aspect of Mtb pathogenesis. Our working model is that MmpL11 is a conserved transporter of mycolic acid-containing lipids. We hypothesize that the biosynthetic pathway for the MmpL11 substrate can be revealed by defining the MmpL11 interactome. This project will define proteins that interact with MmpL11TB demonstrate the biosynthetic pathway leading to production of the MmpL11 substrate. Our preliminary data indicate that MmpL11 interacts with LpqN and TesB, and mutants lacking these proteins share phenotypes with mmpL11 mutants. Both MmpL11 and the biosynthetic pathway leading to the MmpL11TB substrate are potential targets for therapeutic intervention.
Tuberculosis is one of the leading causes of death due to infectious disease. MmpL (Mycobacterial membrane protein large) transporters export lipids to the Mtb cell wall, and our primary interest is in the MmpL11 transporter. Our data suggest that MmpL11 transports 'storage lipids' associated with non-replicating persistence and dormancy, and MmpL11 is required for Mtb to establish a persistent infection. This proposal will identify proteins that interact with MmpL11TB to define the biosynthetic pathway for the MmpL11TB substrate.
| Wright, Catherine C; Hsu, Fong Fu; Arnett, Eusondia et al. (2017) The Mycobacterium tuberculosis MmpL11 Cell Wall Lipid Transporter Is Important for Biofilm Formation, Intracellular Growth, and Nonreplicating Persistence. Infect Immun 85: |
