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.
Highlights
The prevalence of pulmonary nontuberculous mycobacterial (NTM) infections caused by Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) species is increasing worldwide and poses a particular threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis (CF), chronic obstructive pulmonary disease, and bronchiectasis (Park and Olivier, 2015; Parkins and Floto, 2015; Bryant et al, 2016; Floto et al, 2016; Martiniano et al, 2016)
The availability of cidal inhibitors against this new target, some of which have already demonstrated activity in in vivo models of MABSC infection (Dupont et al, 2016; De Groote et al, in revision; Pandya et al, in revision), provides much-needed novel opportunities for the treatment of pulmonary NTM infections. This perspective reflects on the therapeutic potential and promiscuity of MmpL3 in NTM, and discusses recent findings from our laboratories toward understanding the basis for the better activity and looser structure-activity relationship of MmpL3 inhibitors against M. tuberculosis compared to NTM
The observation that the most common resistance mutations identified in both M. tuberculosis and MABSC tend to map to a transmembrane region of MmpL3 overlapping with functional residues required for proton translocation or proton-driven conformational changes in the transporter has led to the hypothesis that inhibitors might target the proton relay site of MmpL3 (Belardinelli et al, 2016)
Summary
The prevalence of pulmonary nontuberculous mycobacterial (NTM) infections caused by Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) species is increasing worldwide and poses a particular threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis (CF), chronic obstructive pulmonary disease, and bronchiectasis (Park and Olivier, 2015; Parkins and Floto, 2015; Bryant et al, 2016; Floto et al, 2016; Martiniano et al, 2016). The availability of cidal inhibitors against this new target, some of which have already demonstrated activity in in vivo models of MABSC infection (Dupont et al, 2016; De Groote et al, in revision; Pandya et al, in revision), provides much-needed novel opportunities for the treatment of pulmonary NTM infections. This perspective reflects on the therapeutic potential and promiscuity of MmpL3 in NTM, and discusses recent findings from our laboratories toward understanding the basis for the better activity and looser structure-activity relationship of MmpL3 inhibitors against M. tuberculosis compared to NTM
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