Therapeutic Potential of the Mycobacterium tuberculosis Mycolic Acid Transporter, MmpL3

Synergistic Interactions of MmpL3 Inhibitors with Antitubercular Compounds In Vitro

“…In recent years, the screening of compound libraries against M. tuberculosis and nontuberculous mycobacteria in culture has identified a number of novel chemical entities with potent mycobactericidal activity whose primary target appears to be the essential mycolic acid transporter MmpL3 (1–4). Among these novel chemical scaffolds, diamine- and indolamide-based compounds have emerged as particularly promising on the basis of efficacy, tolerability, and pharmacological properties (2, 5–7).…”

“…Among these novel chemical scaffolds, diamine- and indolamide-based compounds have emerged as particularly promising on the basis of efficacy, tolerability, and pharmacological properties (2, 5–7). The potency of these compounds is owed at least in part to the exquisite vulnerability of the MmpL3 transporter both in vitro and in vivo (1). Indeed, the inhibition of MmpL3 results in the abolition of the export of mycolic acids to the outer membrane and in the rapid killing of the bacilli (1, 8).…”

“…The potency of these compounds is owed at least in part to the exquisite vulnerability of the MmpL3 transporter both in vitro and in vivo (1). Indeed, the inhibition of MmpL3 results in the abolition of the export of mycolic acids to the outer membrane and in the rapid killing of the bacilli (1, 8). Whether the important changes in the cell envelope composition of M.…”

“…By allowing the dosages of all of these drugs to be reduced, MmpL3 inhibitors, when used in combination, may have the potential to significantly improve the tolerability and efficacy of the drug regimens used in the treatment of drug-susceptible and multidrug-resistant TB infections and of TB/HIV coinfections. These considerations and the potential that MmpL3 inhibitors have to reduce TB treatment duration (1) provide a strong incentive to further evaluate combination regimens containing MmpL3 inhibitors in animal models of TB and nontuberculous mycobacterial infections.…”

The diverse family of MmpL transporters in mycobacteria: from regulation to antimicrobial developments

“…The essentiality of mmpL3 for growth in axenic media and for establishing infection in human macrophages or in a mouse model was recently demonstrated using conditional knockdown mutants (Li et al ., ; Degiacomi et al ., ). Moreover, depletion of MmpL3 had a rapid bactericidal effect and rendered M. tuberculosis more susceptible to MmpL3 inhibitors (Li et al ., ). In this context, MmpL3 was recently identified in multiple high‐throughput whole‐cell screens as the target of several antitubercular agents.…”