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.
Keywords: Anti-tubercular agents, Drug-target, Drug discovery, M. tuberculosis, MmpL3, Structure-Activity Relationship.
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