Cell envelope lipid metabolism
The mycobacterial envelope is unique in the bacterial world, conferring to mycobacteria a highly impermeable “coat”, but also in terms of composition and arrangement, consisting of structurally remarkable compounds with a critical role in virulence. Our group contributed to deciphering the architecture and key components of this envelope, including the lipidic mycomembrane and the polysaccharide-rich capsule. Our work focuses on structural elucidation and fine biochemical characterization of the biosynthetic pathways and enzymes involved in their assembly as potential targets for drug development.
<= Organization of the mycobacterial envelope. AG, arabinogalactan; PG, peptidoglycan; GL, granular layer; PM, plasma membrane.
Mycolic acid biosynthesis as validated target
The mycobacterial cell envelope, especially rich in lipids, is unique due to its complex composition and dual membrane structure. Therefore, targeting enzymes involved in the biosynthesis of mycolic acids, the long chain fatty acids, major component of the mycomembrane, is a validated and attractive approach for developing anti-tuberculosis drugs. Focusing on the essential enzyme FAAL32 (also known as FadD32), an acyl-AMP ligase, we applied screening approaches that led to the identification of effective inhibitors against Mycobacterium tuberculosis, currently under development for further therapeutical applications.
Structural features of BVMO from Mycobacterium tuberculosis
Structure-function and substrate selectivity of BVMOs to gain insights into their activity and how to exploit this knowledge to design novel anti-tuberculosis strategies.
Structural and functional characterization of Baeyer-Villiger monooxygenases
Many anti-tuberculosis drugs require bioactivation, notably by Baeyer-Villiger monooxygenases (BVMO). Among those prodrugs, ethionamide targets mycolic acid biosynthesis. Despite their emerging importance, BVMO structural and functional features remain enigmatic. By combining in silico characterization with in vitro protein activity profiling, we uncover the structural framework and substrate preference of Mycobacterium tuberculosis BVMO enzymes. These features ground the molecular basis for expanding the repertoire of BVMO substrates, including prodrugs.
We also investigate the physiological roles and the functional relevance of the BVMO proteins in Mycobacterium tuberculosis adaptation. Our work aims to elucidate how these enzymes contribute to the pathogen’s survival and resistance mechanisms, offering new avenues to combat tuberculosis.