Synthesis and Testing of Analogs of the Tuberculosis Drug Candidate SQ109 against Bacteria and Protozoa: Identification of Lead Compounds against and Malaria Parasites.

SQ109 is a tuberculosis drug candidate that has high potency against and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against , , , , and , as well as against the protozoan parasites , , , , and .

Proton transfer activity of the reconstituted MmpL3 is modulated by substrate mimics and inhibitors.

Transporters belonging to the Resistance-Nodulation-cell Division (RND) superfamily of proteins such as MmpL3 and its analogs are the focus of intense investigations due to their importance in the physiology of species and antimycobacterial drug discovery. These transporters deliver trehalose monomycolates, the precursors of major lipids of the outer membrane, to the periplasm by a proton motive force-dependent mechanism. In this study, we successfully purified, from native membranes, the full-length and the C-terminal truncated MmpL3 and CmpL1 proteins and reconstituted them into proteoliposomes.