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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5198-5207 |
| Number of pages | 10 |
| Journal | Antimicrobial Agents and Chemotherapy |
| Volume | 60 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2016 |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Infectious Diseases
- Pharmacology (medical)
Cite this
Therapeutic potential of the Mycobacterium tuberculosis mycolic acid transporter, MmpL3. / Li, Wei; Obregón-Henao, Andrés; Wallach, Joshua B.; North, E. Jeffrey; Lee, Richard E.; Gonzalez-Juarrero, Mercedes; Schnappinger, Dirk; Jackson, Mary.
In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 9, 01.09.2016, p. 5198-5207.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Therapeutic potential of the Mycobacterium tuberculosis mycolic acid transporter, MmpL3
AU - Li, Wei
AU - Obregón-Henao, Andrés
AU - Wallach, Joshua B.
AU - North, E. Jeffrey
AU - Lee, Richard E.
AU - Gonzalez-Juarrero, Mercedes
AU - Schnappinger, Dirk
AU - Jackson, Mary
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84983509267&partnerID=8YFLogxK
U2 - 10.1128/AAC.00826-16
DO - 10.1128/AAC.00826-16
M3 - Article
C2 - 27297488
AN - SCOPUS:84983509267
VL - 60
SP - 5198
EP - 5207
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 9
ER -