TY - JOUR
T1 - MmpL3 inhibition
T2 - A new approach to treat nontuberculous mycobacterial infections
AU - Sethiya, Jigar P.
AU - Sowards, Melanie A.
AU - Jackson, Mary
AU - North, Elton Jeffrey
N1 - Funding Information:
This project was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases research grant AI116525 and an award from the Cystic Fibrosis Foundation.
Funding Information:
Funding: This project was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases research grant AI116525 and an award from the Cystic Fibrosis Foundation.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow-or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt420, C10) that promote reversion of drug resistance are also reviewed.
AB - Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow-or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt420, C10) that promote reversion of drug resistance are also reviewed.
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U2 - 10.3390/ijms21176202
DO - 10.3390/ijms21176202
M3 - Review article
C2 - 32867307
AN - SCOPUS:85090035933
VL - 21
SP - 1
EP - 25
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 17
M1 - 6202
ER -