Abstract
The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope biogenesis in mycobacteria, required for transport of precursors, trehalose monomycolates (TMMs), is the Mycobacterial membrane protein large 3 (MmpL3). Due to its central role in TMM transport, MmpL3 has been an attractive therapeutic target and a key target for several preclinical agents. In 2019, the first crystal structures of the MmpL3 transporter and its complexes with lipids and inhibitors were reported. These structures revealed several unique structural features of MmpL3 and provided invaluable information on the mechanism of TMM transport. This review aims to highlight the recent advances made in the function of MmpL3 and summarises structural findings. The overall goal is to provide a mechanistic perspective of MmpL3-mediated lipid transport and inhibition, and to highlight the prospects for potential antituberculosis therapies.
Highlights
Tuberculosis (TB) is one of the deadliest infectious human diseases and is caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb)
The emergence of pathogenic bacterial strains that are resistant to multiple antibiotics warrants the search for new drugs to treat infectious diseases
In line with this, the past decade has witnessed a myriad of studies dedicated to identifying new chemical scaffolds
Summary
Tuberculosis (TB) is one of the deadliest infectious human diseases and is caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb). The three main components of the cell wall are peptidoglycan, arabinogalactan and mycomembrane, which contains mycolic acids and various glycolipids. These cell wall components have been shown to interfere with host phagosome maturation and are important virulence factors for Mtb pathogenesis [6,7]. For these reasons, investigating the biosynthesis or assembly of mycobacterial cell envelope components and their inhibition has great potential to yield very effective antitubercular drugs. Proteins that associate with mycomembrane are not well characterised and emerging methodologies such as in vivo photo cross-linking in conjunction with quantitative proteomics offer a great potentiality for identifying novel targets in this pathway [8]
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