title: MmpL3 Inhibitors: Diverse Chemical Scaffolds Inhibit the Same Target.
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.
authors.affiliation: Department of Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le A. Moro 5, Rome, Italy. giovanna.poce@uniroma1.it.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Poce
authors.forename: Sara
authors.initials: S
authors.lastname: Consalvi
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D026901:Membrane Transport Proteins; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009171:Mycolic Acids / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; C000599913:MmpL3 protein, Mycobacterium tuberculosis; D009171:Mycolic Acids