Molecular insights into anti-mycobacterial compounds targeting MmpL3.

Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that poses a severe threat to human health. Mycobacterial infections require long-term treatment and have a multitude of associated undesirable effects. Therefore, finding new targets and new anti-TB drugs is of great importance. One promising target is Mycobacterial membrane protein Large 3 (MmpL3), a member of the resistance-nodulation-division (RND) class of transporters located in the inner membrane (IM). MmpL3 transports trehalose monomycolates (TMMs), an abundant outer membrane lipids of Mtb, from the IM to the periplasmic space. Indole-2-carboxamides have already been demonstrated to inhibit MmpL3, but display limited bioavailability in vivo. To gain more insight into their potential for further drug development, we carried out molecular docking for 10 modified compounds based on indole-2-carboxamides but containing higher ratios of heteroatoms. The docking results show that acetamide-based compounds have high affinity, which is consistent with experiment results that they have minimum inhibitory concentration. Taking a broader view, we also used molecular dynamics simulations to investigate the behavior of TMMs, substrates of MmpL3, in the IM. We found that, unlike phospholipids, the longer of the two acyl chains of TMM can extend into the middle of the two leaflets of the IM as well as occasionally insert into the opposite leaflet.