Identification of covalent inhibitors that disrupt M. tuberculosis growth by targeting multiple serine hydrolases involved in lipid metabolism.

Autor:	Babin BM; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA., Keller LJ; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA., Pinto Y; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Divisions of Hematology and Blood & Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA., Li VL; Department of Chemistry, Stanford University, Stanford, CA 94305, USA., Eneim AS; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA., Vance SE; Divisions of Hematology and Blood & Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA., Terrell SM; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA., Bhatt AS; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Divisions of Hematology and Blood & Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA., Long JZ; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA., Bogyo M; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: mbogyo@stanford.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2022 May 19; Vol. 29 (5), pp. 897-909.e7. Date of Electronic Publication: 2021 Oct 01.
DOI:	10.1016/j.chembiol.2021.08.013
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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