Identification of cell wall synthesis inhibitors active against Mycobacterium tuberculosis by competitive activity-based protein profiling.

Autor:	Li M; Department of Pharmacological Sciences and Immunology Stony Brook University, Stony Brook, NY 11790, USA., Patel HV; Department of Microbiology and Immunology Stony Brook University, Stony Brook, NY 11790, USA., Cognetta AB 3rd; Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA., Smith TC 2nd; Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA., Mallick I; Aix-Marseille Université, CNRS, LISM, IMM FR3479, 13402 Marseille, France., Cavalier JF; Aix-Marseille Université, CNRS, LISM, IMM FR3479, 13402 Marseille, France., Previti ML; Department of Pharmacological Sciences and Immunology Stony Brook University, Stony Brook, NY 11790, USA., Canaan S; Aix-Marseille Université, CNRS, LISM, IMM FR3479, 13402 Marseille, France., Aldridge BB; Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA., Cravatt BF; Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA., Seeliger JC; Department of Pharmacological Sciences and Immunology Stony Brook University, Stony Brook, NY 11790, USA. Electronic address: jessica.seeliger@stonybrook.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2022 May 19; Vol. 29 (5), pp. 883-896.e5. Date of Electronic Publication: 2021 Oct 01.
DOI:	10.1016/j.chembiol.2021.09.002
Abstrakt:	The identification and validation of a small molecule's targets is a major bottleneck in the discovery process for tuberculosis antibiotics. Activity-based protein profiling (ABPP) is an efficient tool for determining a small molecule's targets within complex proteomes. However, how target inhibition relates to biological activity is often left unexplored. Here, we study the effects of 1,2,3-triazole ureas on Mycobacterium tuberculosis (Mtb). After screening ∼200 compounds, we focus on 4 compounds that form a structure-activity series. The compound with negligible activity reveals targets, the inhibition of which is functionally less relevant for Mtb growth and viability, an aspect not addressed in other ABPP studies. Biochemistry, computational docking, and morphological analysis confirms that active compounds preferentially inhibit serine hydrolases with cell wall and lipid metabolism functions and that disruption of the cell wall underlies biological activity. Our findings show that ABPP identifies the targets most likely relevant to a compound's antibacterial activity. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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