Covalent Sortase A Inhibitor ML346 Prevents Infection of

Overview

Journal RSC Med Chem

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 Mar 21

PMID 35308030

Authors

Xiang-Na Guan

Tao Zhang

Teng Yang

Ze Dong

Song Yang

Lefu Lan

Jianhua Gan

Cai-Guang Yang

Affiliations

Soon will be listed here.

Abstract

The housekeeping sortase A (SrtA), a membrane-associated cysteine transpeptidase, is responsible for anchoring surface proteins to the cell wall peptidoglycan in Gram-positive bacteria. This process is essential for the regulation of bacterial virulence and pathogenicity. Therefore, SrtA is considered to be an ideal target for antivirulence therapy. In this study, we report that ML346, a compound with a barbituric acid and cinnamaldehyde scaffold, functions as an irreversible inhibitor of SrtA (SrtA) and SrtA (SrtA) at low micromolar concentrations. According to our X-ray crystal structure of the SrtA/ML346 complex (Protein Data Bank ID: 7V6K), ML346 covalently modifies the thiol group of Cys208 in the active site of SrtA. Importantly, ML346 significantly attenuated the virulence phenotypes of and exhibited inhibitory effects on larva infection caused by . Collectively, our results indicate that ML346 has potential for development as a covalent antivirulence agent for treating infections, including methicillin-resistant .

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