Inhibition Mechanism of Anti-TB Drug SQ109: Allosteric Inhibition of TMM Translocation of Mycobacterium Tuberculosis MmpL3 Transporter.

ABSTRACT: The mycolic acid transporter MmpL3 is driven by proton motive forces (PMF) and functions via an antiport mechanism. Although the crystal structures of the Mycobacterium smegmatis MmpL3 transporter alone and in complex with a trehalose monomycolate (TMM) substrate and an antituberculosis drug candidate SQ109 under Phase 2b-3 Clinical Trials are available, no water and no conformational change in MmpL3 were observed in these structures to explain SQ109's inhibition mechanism of proton and TMM transportation. In this study, molecular dynamics simulations of both apo form and inhibitor-bound MmpL3 in an explicit membrane were used to decipher the inhibition mechanism of SQ109. In the apo system, the close-open motion of the two TM domains, likely driven by the proton translocation, driv

SUBMITTER: Carbone J 

PROVIDER: S-EPMC10466384 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature