2. Academic Validation
  3. Structure-Based Development of a Covalent Inhibitor Targeting Streptococcus Pyogenes over Staphylococcus Aureus Sortase A

Structure-Based Development of a Covalent Inhibitor Targeting Streptococcus Pyogenes over Staphylococcus Aureus Sortase A

  • Chemistry. 2025 Mar 12:e202500464. doi: 10.1002/chem.202500464.
Hailing Zhou 1 2,  Ziqi Yuan 1 2,  Xiang-Na Guan 1 2,  Chuan Yue 3,  Wei Wu 1 2,  Lefu Lan 4 2,  Jianhua Gan 5,  Tao Zhang 1 2,  Cai-Guang Yang 1 3 4 2 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 5 School of Life Sciences, Fudan University, Shanghai, 200433, China.
  • 6 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China.
PMID: 40072260 DOI: 10.1002/chem.202500464
Abstract

Sortase A (SrtA), a cysteine transpeptidase critical for surface protein anchoring in Gram-positive pathogens, represents an attractive antivirulence target. While covalent SrtA inhibitors show therapeutic potential, existing compounds lack species selectivity. Through structure-guided design, we developed T10, a covalent inhibitor selectively targeting Streptococcus pyogenes SrtA (SpSrtA) over Staphylococcus aureus SrtA (SaSrtA). Molecular docking revealed that shortening a "C=C" bond in lead compound ML346 eliminated SaSrtA inhibition due to steric hindrance from W194, while maintaining SpSrtA binding. X-ray crystallography confirmed T10's covalent modification of Cys208 in SpSrtA. T10 demonstrated two fold enhanced inhibitory potency and species-specific disruption of M-protein anchoring and biofilm formation in Streptococcus pyogenes, without affecting Staphylococcus aureus viability. In a Galleria mellonella Infection model, T10 conferred potent protection against lethal Infection. This work demonstrates the development of narrow-spectrum antivirulence agents through a structure-based rational strategy.

Keywords

Sortase A; Streptococcus pyogenes; covalent inhibitors; narrow-spectrum anti-virulence agent; structure-activity relationships.

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