Intermembrane transport of lipids and metabolites by mycobacterial MmpL protein complexes

University Of Oklahoma, Norman OK

Investigators

Abstract

PROJECT DESCRIPTION Infections caused by Mycobacterium spp. are very challenging to treat and multidrug-resistant strains rapidly spread in human populations. Intrinsic and acquired multidrug resistance of these pathogens demand new fundamental insights into underlying molecular mechanisms that will facilitate the discovery of new therapeutics. This project is focused on understanding the mechanisms of lipid/metabolite and drug transport in Mycobacterium tuberculosis and related mycobacteria. MmpL protein complexes are major contributors to these processes and are important targets in current drug discovery efforts. The long-term goal of this project is to characterize the mechanism and functions of mycobacterial MmpL transporters alone and in the context of their protein complexes. The major objective of this application is to establish the molecular mechanisms and structures of MmpL3, MmpL5 and MmpL7 transporters and their complexes with interacting partner proteins. These three transporters have distinct substrate specificities, functions, and mechanisms, but also share certain common traits. We will use the similarities and differences between these transporters to gain mechanistic insights into their physiological functions. The specific aims of this application are: 1) Define the transport activities of MmpL transporters. 2) Reconstitute and characterize the activities of MmpL transporters in complexes with protein partners. 3) Define structures of MmpL transporters alone and in complexes with interacting partners. These studies will be performed by a multi-disciplinary team of investigators: Edward Yu (Structural Biology), Mary Jackson (Microbiology and Mycobacterial Physiology), Benjamin Swarts (Synthetic Chemistry) and Helen Zgurskaya (Biochemistry and Membrane Transport). The major outcome of the proposed studies will be novel structural and mechanistic insights into MmpL transporters and their roles in the assembly of the mycobacterial outer membrane and antibiotic resistance. If successful, the proposed studies will facilitate the development of new anti-mycobacterial agents.