Babin_2022_Cell.Chem.Biol_29_897

Reference

Title : Identification of covalent inhibitors that disrupt M. tuberculosis growth by targeting multiple serine hydrolases involved in lipid metabolism - Babin_2022_Cell.Chem.Biol_29_897
Author(s) : Babin BM , Keller LJ , Pinto Y , Li VL , Eneim AS , Vance SE , Terrell SM , Bhatt AS , Long JZ , Bogyo M
Ref : Cell Chemical Biology , 29 :897 , 2022
Abstract :

The increasing incidence of antibiotic-resistant Mycobacterium tuberculosis infections is a global health threat necessitating the development of new antibiotics. Serine hydrolases (SHs) are a promising class of targets because of their importance for the synthesis of the mycobacterial cell envelope. We screen a library of small molecules containing serine-reactive electrophiles and identify narrow-spectrum inhibitors of M. tuberculosis growth. Using these lead molecules, we perform competitive activity-based protein profiling and identify multiple SH targets, including enzymes with uncharacterized functions. Lipidomic analyses of compound-treated cultures reveal an accumulation of free lipids and a substantial decrease in lipooligosaccharides, linking SH inhibition to defects in cell envelope biogenesis. Mutant analysis reveals a path to resistance via the synthesis of mycocerates, but not through mutations to SH targets. Our results suggest that simultaneous inhibition of multiple SH enzymes is likely to be an effective therapeutic strategy for the treatment of M. tuberculosis infections.

PubMedSearch : Babin_2022_Cell.Chem.Biol_29_897
PubMedID: 34599874

Related information

Inhibitor JCP276

Citations formats

Babin BM, Keller LJ, Pinto Y, Li VL, Eneim AS, Vance SE, Terrell SM, Bhatt AS, Long JZ, Bogyo M (2022)
Identification of covalent inhibitors that disrupt M. tuberculosis growth by targeting multiple serine hydrolases involved in lipid metabolism
Cell Chemical Biology 29 :897

Babin BM, Keller LJ, Pinto Y, Li VL, Eneim AS, Vance SE, Terrell SM, Bhatt AS, Long JZ, Bogyo M (2022)
Cell Chemical Biology 29 :897