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Therapeutic Potential of the Mycobacterium tuberculosis Mycolic Acid Transporter, MmpL3.

TitleTherapeutic Potential of the Mycobacterium tuberculosis Mycolic Acid Transporter, MmpL3.
Publication TypeJournal Article
Year of Publication2016
AuthorsLi W, Obregón-Henao A, Wallach JB, E North J, Lee RE, Gonzalez-Juarrero M, Schnappinger D, Jackson M
JournalAntimicrob Agents Chemother
Volume60
Issue9
Pagination5198-207
Date Published2016 09
ISSN1098-6596
KeywordsAnimals, Antitubercular Agents, Bacterial Load, Bacterial Proteins, Biological Transport, Ciprofloxacin, Disease Models, Animal, Doxycycline, Female, Gene Expression, Gene Knockdown Techniques, Humans, Isoniazid, Lung, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Microbial Sensitivity Tests, Microbial Viability, Mycobacterium tuberculosis, Mycolic Acids, Rifampin, Tuberculosis, Multidrug-Resistant, Tuberculosis, Pulmonary
Abstract

In recent years, whole-cell-based screens for novel small molecule inhibitors active against Mycobacterium tuberculosis in culture followed by the whole-genome sequencing of spontaneous resistant mutants have identified multiple chemical scaffolds thought to kill the bacterium through the inactivation of the mycolic acid transporter, MmpL3. Consistent with the fact that MmpL3 is required for the formation of the mycobacterial outer membrane, we have conclusively shown in this study, using conditionally regulated knockdown mutants, that mmpL3 is required for the replication and viability of M. tuberculosis, both under standard laboratory growth conditions and during the acute and chronic phases of infection in mice. Speaking for the vulnerability of this target, silencing mmpL3 had a rapid bactericidal effect on actively replicating cells in vitro and reduced by 3 to 5 logs in less than 4 weeks the bacterial loads of acutely and chronically infected mouse lungs, respectively. Depletion of MmpL3 further rendered M. tuberculosis hypersusceptible to MmpL3 inhibitors. The exquisite vulnerability of MmpL3 at all stages of the infection establishes this transporter as an attractive new target with the potential to improve and shorten current drug-susceptible and drug-resistant tuberculosis chemotherapies.

DOI10.1128/AAC.00826-16
Alternate JournalAntimicrob Agents Chemother
PubMed ID27297488
PubMed Central IDPMC4997843
Grant ListF31 NR013813 / NR / NINR NIH HHS / United States
R01 AI116525 / AI / NIAID NIH HHS / United States

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