Download MendeleyCovalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella.
Guan, X.N., Zhang, T., Yang, T., Dong, Z., Yang, S., Lan, L., Gan, J., Yang, C.G.(2022) RSC Med Chem 13: 138-149
- PubMed: 35308030
- DOI: https://doi.org/10.1039/d1md00316j
- Primary Citation of Related Structures:
7V6K - PubMed 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 Staphylococcus aureus SrtA ( Sa SrtA) and Streptococcus pyogenes SrtA ( Sp SrtA) in vitro at low micromolar concentrations. According to our X-ray crystal structure of the Sp SrtA ΔN81 /ML346 complex (Protein Data Bank ID: 7V6K), ML346 covalently modifies the thiol group of Cys208 in the active site of Sp SrtA. Importantly, ML346 significantly attenuated the virulence phenotypes of S. aureus and exhibited inhibitory effects on Galleria mellonella larva infection caused by S. aureus . Collectively, our results indicate that ML346 has potential for development as a covalent antivirulence agent for treating S. aureus infections, including methicillin-resistant S. aureus .
Organizational Affiliation:
Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 China yangcg@simm.ac.cn.
