Project Grant R01AI187294

The University of Oklahoma, through its Office of Research Administration, was awarded a $811,396 Project Grant (R01AI187294) by the National Institute of Allergy and Infectious Diseases (CFDA 93.855) to conduct research on the transport mechanisms and structures of MMPL proteins in Mycobacterium tuberculosis and related mycobacteria. The goal is to gain mechanistic insights into the physiological functions of these transporters, which contribute to the intrinsic and acquired multidrug resistance of these pathogens. The research will be performed by a multi-disciplinary team that includes experts in structural biology, microbiology, synthetic chemistry, and membrane transport. The project has three specific aims: 1) define the transport activities of MMPL transporters, 2) reconstitute and characterize the activities of MMPL transporters in complexes with protein partners, and 3) define the structures of MMPL transporters alone and in complexes with interacting partners. Under this grant, Case Western Reserve University will use cryo-EM to determine the structures of the M. smegmatis and M. tuberculosis MMPL transporters, while Colorado State University will conduct in cellulo experiments to generate recombinant strains and test the impact of defined mutations on MMPL transport activity, drug susceptibility, and protein interactions.