MmpL3 Inhibition: A New Approach to Treat Nontuberculous Mycobacterial Infections

Abstract

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, SMARt-420, C10) that promote reversion of drug resistance are also reviewed.

Mab_3083c Is a Homologue of RNase J and Plays a Role in Colony Morphotype, Aggregation, and Sliding Motility of Mycobacterium abscessus

“…Mycobacterium abscessus is a rapid-growing nontuberculous Mycobacterium (NTM) and is often present in soil and water [ 1 , 2 ]. It has been found to infect lung, skin, and soft tissue, especially in immunocompromised patients [ 3 , 4 , 5 , 6 ] and is the second most common bacterial species isolated from cystic fibrosis patients [ 7 , 8 ]. The prevalence of M. abscessus infection is increasing in hospitals in Taiwan [ 9 , 10 ].…”

“…Fatal M. abscessus infections have also been reported, especially after lung transplantation [ 16 , 17 ]. Several reports have indicated that M. abscessus can infect both immunodeficient and immunocompetent patients [ 2 , 6 , 18 ].…”

Pipeline of anti‐Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

“…MmpL3, the integral membrane RND‐type transporter required for mature mycolic acids to be translocated under the form of trehalose monomycolates (TMMs) from the cytoplasm to the periplasmic space 57 has been the object of much attention in recent years as the target of many new chemical entities with promising antitubercular activity. Interestingly, and as will be illustrated in Section 4, many of these new inhibitors also proved active against M. abscessus, M. avium or both complexes 26,58 . Other M. abscessus actives targeting MmpL3 were identified by de novo phenotypic screen of compound libraries 59,60 .…”

“…Several recent reviews have considered the challenges and opportunities associated with drug repurposing for the treatment of M. abscessus pulmonary infections 3,7,8,16‐24 . Only a few articles, in contrast, discuss the novel compounds that are being developed against these emerging pathogens 25‐27 . We herein review current knowledge of validated drug targets in M. abscessus and focus on the discovery, structure–activity relationship, in vitro and in vivo activity, mode of action, and pharmacokinetics of the most promising new chemical classes of anti‐ M. abscessus agents.…”

Rufomycin Exhibits Dual Effects Against Mycobacterium abscessus Infection by Inducing Host Defense and Antimicrobial Activities

“…Nontuberculous mycobacteria (NTM) are a diverse group of more than 190 bacilli, other than Mycobacterium tuberculosis complex ( Porvaznik et al, 2017 ). Although NTM are ubiquitously found in the environments, some of them are able to cause disease in immunocompetent and immunocompromised persons ( Simons et al, 2011 ; Wassilew et al, 2016 ; Porvaznik et al, 2017 ; Maiz Carro et al, 2018 ; Sethiya et al, 2020 ). The prevalence and incidence of NTM diseases are increasing, thus having emerged as important pathogens worldwide ( Wassilew et al, 2016 ; To et al, 2020 ).…”