MmpL3 Inhibitors: Diverse Chemical Scaffolds Inhibit the Same Target

Mini Reviews in Medicinal Chemistry
Giovanna PoceMariangela Biava

Abstract

MmpL3 belongs to the Resistance, Nodulation and Division (RND) superfamily whose role in mycobacteria is the formation of the outer membrane. Indeed, it has been shown that MmpL3 is associated with the export of mycolic acids in the form of trehalose monomycolates (TMM) to the periplasmic space or the outer membrane. In the last few years several whole cell-based screenings of compound libraries brought by a number of diverse chemical scaffolds active against M. tuberculosis (Mtb) that surprisingly share MmpL3 as target. The diverse identified pharmacophores owe important differences among each other, in fact while some of them display inhibitory activity against pathogens that are devoid of mycolic acids and are active against non-replicating Mtb bacilli, some others specifically target mycobacteria and do not kill non-replicating bacilli. The scope of this review is to provide the recent advances in MmpL3 inhibitor discovery with a special focus on structure activity relationship (SAR) studies in order to provide information that could help in developing novel membrane-active anti- TB agents. Moreover, this review will provide the most recent insights into the modes of action of the MmpL3 inhibitors.

Citations

Jul 18, 2018·Antimicrobial Agents and Chemotherapy·Adrian RichterYossef Av-Gay
Jul 15, 2020·Biochemical Society Transactions·Jani R Bolla
Apr 18, 2018·Antimicrobial Agents and Chemotherapy·Huiqing ZhengRobert B Abramovitch
Oct 9, 2018·Frontiers in Microbiology·Mary A De GrooteUrs A Ochsner
Aug 14, 2019·Antimicrobial Agents and Chemotherapy·John T WilliamsRobert B Abramovitch
Sep 28, 2017·Archives of Microbiology·Padmani Sandhu, Yusuf Akhter
Oct 18, 2019·ACS Medicinal Chemistry Letters·Giovanna PoceMariangela Biava

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