Recent advances in mycobacterial membrane protein large 3 inhibitor drug design for mycobacterial infections

Tuberculosis and nontuberculous mycobacterial infections are notoriously difficult to treat, requiring long-courses of intensive multi-drug therapies associated with adverse side effects. To identify better therapeutics, whole cell screens have identified novel pharmacophores, a surprisingly high number of which target an essential lipid transporter known as MmpL3.

This paper summarizes what is known about MmpL3, its mechanism of lipid transport and therapeutic potential, and provides an overview of the different classes of MmpL3 inhibitors currently under development. It further describes the assays available to study MmpL3 inhibition by these compounds.

MmpL3 has emerged as a target of high therapeutic value. Accordingly, several classes of MmpL3 inhibitors are currently under development with one drug candidate (SQ109) having undergone a Phase 2b clinical study. The hydrophobic character of most MmpL3 series identified to date seems to drive antimycobacterial potency resulting in poor bioavailability, which is a significant impediment to their development. There is also a need for more high-throughput and informative assays to elucidate the precise mechanism of action of MmpL3 inhibitors and drive the rational optimization of analogues.