Abstract
Nontuberculous mycobacterial (NTM) pulmonary infections are emerging as a global health problem and pose a threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) species account for 70-95% of the pulmonary NTM infections worldwide. Treatment options for these pathogens are limited, involve lengthy multidrug regimens of 12-18 months with parenteral and oral drugs, and their outcome is often suboptimal. Development of new drugs and improved regimens to treat NTM infections are thus greatly needed. In the last 2 years, the screening of compound libraries against M. abscessus in culture has led to the discovery of a number of different chemotypes that target MmpL3, an essential inner membrane transporter involved in the export of the building blocks of the outer membrane of all mycobacteria known as the mycolic acids. This perspective reflects on the therapeutic potential of MmpL3 in Mycobacterium tuberculosis and NTM and the possible reasons underlying the outstanding promiscuity of this target. It further analyzes the physiological and structural factors that may account for the apparent looser structure-activity relationship of some of these compound series against M. tuberculosis compared to NTM.
| Original language | English (US) |
|---|---|
| Article number | 1547 |
| Journal | Frontiers in Microbiology |
| Volume | 9 |
| Issue number | JUL |
| DOIs | |
| State | Published - Jul 10 2018 |
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All Science Journal Classification (ASJC) codes
- Microbiology
- Microbiology (medical)
Cite this
MmpL3 as a target for the treatment of drug-resistant nontuberculous mycobacterial infections. / Li, Wei; Yazidi, Amira; Pandya, Amitkumar N.; Hegde, Pooja; Tong, Weiwei; de Moura, Vinicius Calado Nogueira; North, E. Jeffrey; Sygusch, Jurgen; Jackson, Mary.
In: Frontiers in Microbiology, Vol. 9, No. JUL, 1547, 10.07.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MmpL3 as a target for the treatment of drug-resistant nontuberculous mycobacterial infections
AU - Li, Wei
AU - Yazidi, Amira
AU - Pandya, Amitkumar N.
AU - Hegde, Pooja
AU - Tong, Weiwei
AU - de Moura, Vinicius Calado Nogueira
AU - North, E. Jeffrey
AU - Sygusch, Jurgen
AU - Jackson, Mary
PY - 2018/7/10
Y1 - 2018/7/10
N2 - Nontuberculous mycobacterial (NTM) pulmonary infections are emerging as a global health problem and pose a threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) species account for 70-95% of the pulmonary NTM infections worldwide. Treatment options for these pathogens are limited, involve lengthy multidrug regimens of 12-18 months with parenteral and oral drugs, and their outcome is often suboptimal. Development of new drugs and improved regimens to treat NTM infections are thus greatly needed. In the last 2 years, the screening of compound libraries against M. abscessus in culture has led to the discovery of a number of different chemotypes that target MmpL3, an essential inner membrane transporter involved in the export of the building blocks of the outer membrane of all mycobacteria known as the mycolic acids. This perspective reflects on the therapeutic potential of MmpL3 in Mycobacterium tuberculosis and NTM and the possible reasons underlying the outstanding promiscuity of this target. It further analyzes the physiological and structural factors that may account for the apparent looser structure-activity relationship of some of these compound series against M. tuberculosis compared to NTM.
AB - Nontuberculous mycobacterial (NTM) pulmonary infections are emerging as a global health problem and pose a threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) species account for 70-95% of the pulmonary NTM infections worldwide. Treatment options for these pathogens are limited, involve lengthy multidrug regimens of 12-18 months with parenteral and oral drugs, and their outcome is often suboptimal. Development of new drugs and improved regimens to treat NTM infections are thus greatly needed. In the last 2 years, the screening of compound libraries against M. abscessus in culture has led to the discovery of a number of different chemotypes that target MmpL3, an essential inner membrane transporter involved in the export of the building blocks of the outer membrane of all mycobacteria known as the mycolic acids. This perspective reflects on the therapeutic potential of MmpL3 in Mycobacterium tuberculosis and NTM and the possible reasons underlying the outstanding promiscuity of this target. It further analyzes the physiological and structural factors that may account for the apparent looser structure-activity relationship of some of these compound series against M. tuberculosis compared to NTM.
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UR - http://www.scopus.com/inward/citedby.url?scp=85049842507&partnerID=8YFLogxK
U2 - 10.3389/fmicb.2018.01547
DO - 10.3389/fmicb.2018.01547
M3 - Article
VL - 9
JO - Frontiers in Microbiology
JF - Frontiers in Microbiology
SN - 1664-302X
IS - JUL
M1 - 1547
ER -