MmpL3 as a Target for the Treatment of Drug-Resistant Nontuberculous Mycobacterial Infections

• Published in: Frontiers in microbiology Vol. 9; p. 1547
• Main Authors: Li, Wei, Yazidi, Amira, Pandya, Amitkumar N, Hegde, Pooja, Tong, Weiwei, Calado Nogueira de Moura, Vinicius, North, E Jeffrey, Sygusch, Jurgen, Jackson, Mary
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 10.07.2018
• Subjects: drug development; Microbiology; MmpL3; Mycobacterium abscessus; mycolic acids; nontuberculous mycobacteria; drug development; mycolic acids; nontuberculous mycobacteria; Mycobacterium abscessus; MmpL3
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2018.01547

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. complex (MAC) and 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 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 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 compared to NTM.