S288T mutation altering MmpL3 periplasmic domain channel and H-bond network: a novel dual drug resistance mechanism

Abstract

Mycobacterial membrane proteins Large 3 (MmpL3) is responsible for the transport of mycobacterial acids out of cell membrane to form cell wall, which is essential for the survival of Mycobacterium tuberculosis (Mtb) and has become a potent anti-tuberculosis target. Drug resistance has always been the bottleneck problem in clinical treatment of tuberculosis. The S288T mutant of MmpL3 shows signi cant resistance to the inhibitor SQ109, while the speci c action mechanism remains unclear. In this work, molecular dynamics (MD) and quantum mechanics (QM) simulations both were performed to compare inhibitor (i.e., SQ109) recognition, motion characteristics and H-bond energy change of MmpL3 after S288T mutation. The results show that MmpL3 S288T mutation causes local conformational change with little effect on the global structure. With MmpL3 bound by SQ109 inhibitor, the distance between D710 and R715 increases resulting in H-bond destruction, but their interactions and proton transfer function are still restored. In addition, the rotation of Y44 in the S288T mutant leads to an obvious bend in the periplasmic domain channel and an increased number of contact residues, reducing substrate transport e ciency. This work not only provides a possible dual drug resistance mechanism of MmpL3 S288T mutant, but also aids the development of novel anti-tuberculosis inhibitors.