Abstract
SummaryTuberculosis (TB) is the leading cause of death from a single infectious agent and in 2019 an estimated 10 million people worldwide contracted the disease. Although treatments for TB exist, continual emergence of drug-resistant variants necessitates urgent development of novel antituberculars. An important new target is the lipid transporter MmpL3, which is required for construction of the unique cell envelope that shields Mycobacterium tuberculosis (Mtb) from the immune system. However, a structural understanding of the mutations in Mtb MmpL3 that confer resistance to the many preclinical leads is lacking, hampering efforts to circumvent resistance mechanisms. Here, we present the cryoelectron microscopy structure of Mtb MmpL3 and use it to comprehensively analyze the mutational landscape of drug resistance. Our data provide a rational explanation for resistance variants local to the central drug binding site, and also highlight a potential alternative route to resistance operating within the periplasmic domain.
Highlights
Tuberculosis (TB) remains the leading cause of death attributable to a single pathogen (World Health Organization, 2020)
In conjunction with the recently reported structures of membrane protein large 3 (MmpL3) from Mycobacterium smegmatis (Msmg), our work provides a foundation for structure-based drug design against Mycobacterium tuberculosis (Mtb) MmpL3, guided by an enhanced appreciation of the underlying mutational landscape
Cryo-EM structure of Mtb MmpL3 To obtain the structure of Mtb MmpL3 we generated a C-terminally truncated construct capable of being overexpressed in E. coli (Figure S1A)
Summary
Tuberculosis (TB) remains the leading cause of death attributable to a single pathogen (World Health Organization, 2020). Compounding this is the emergence and endemic nature of several drug-resistant Mycobacterium tuberculosis (Mtb) strains (Udwadia et al, 2012; Velayati et al, 2009). MmpL3 is an essential protein belonging to the resistancenodulation-division (RND) superfamily of transporters (DeJesus et al, 2017; Domenech et al, 2005). TMM transport is essential for the formation of the unique Mycobacterium cell envelope that functions as the main physical barrier to drug entry and neutralization by the immune system (Dulberger et al, 2020; Jackson, 2014). The driving force for TMM export is thought to come from the proton-motive force (PMF) established across the inner membrane (Grzegorzewicz et al, 2012; Szekely and Cole, 2016), the precise mechanism by which the PMF drives lipid export remains unclear
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