Therapeutic Potential of the Mycobacterium tuberculosis Mycolic Acid Transporter, MmpL3.
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.
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
Wei
W
Li
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
Andrés
A
Obregón-Henao
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
Joshua B
JB
Wallach
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
E Jeffrey
EJ
North
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Richard E
RE
Lee
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
Mercedes
M
Gonzalez-Juarrero
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
Dirk
D
Schnappinger
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA Mary.Jackson@colostate.edu.
Mary
M
Jackson
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D058491:Bacterial Load / Q000187:drug effects; D001426:Bacterial Proteins / Q000235:genetics*; D001692:Biological Transport; D002939:Ciprofloxacin / Q000494:pharmacology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D009171:Mycolic Acids; D012293:Rifampin / Q000494:pharmacology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; C000599913:MmpL3 protein, Mycobacterium tuberculosis; D009171:Mycolic Acids; D002939:Ciprofloxacin; D004318:Doxycycline; D007538:Isoniazid; D012293:Rifampin