Calcium-binding motif-mediated binding of redundant calcium offers a chimeolysin enhanced bactericidal activity and extended host range under physiological conditions

Autor: Minghui Jia, Wanli Zhou, Dehua Luo, Heng Xue, Fen Hu, Xiaomei Zhang, Zirong Zhao, Mingyue Zhong, Xinfeng Li, Jin He, Hongping Wei, Hang Yang
Rok vydání: 2023
Předmět:
Zdroj: Journal of Antimicrobial Chemotherapy. 78:1182-1190
ISSN: 1460-2091
0305-7453
DOI: 10.1093/jac/dkad059
Popis: Objectives Calcium-binding motifs are shared by multiple bacteriophage lysins; however, the influence of calcium on the enzymatic activity and host range of these enzymes is still not understood. To address this, ClyF, a chimeric lysin with a putative calcium-binding motif, was used as a model for in vitro and in vivo investigations. Methods The concentration of calcium bound to ClyF was determined by atomic absorption spectrometry. The influence of calcium on the structure, activity and host range of ClyF was assessed by circular dichroism and time–kill assays. The bactericidal activity of ClyF was evaluated in various sera and a mouse model of Streptococcus agalactiae bacteraemia. Results ClyF has a highly negatively charged surface around the calcium-binding motif that can bind extra calcium, thereby increasing the avidity of ClyF for the negatively charged bacterial cell wall. In line with this, ClyF exhibited significantly enhanced staphylolytic and streptolytic activity in various sera containing physiological calcium, including human serum, heat-inactivated human serum, mouse serum and rabbit serum. In a mouse model of S. agalactiae bacteraemia, intraperitoneal administration of a single dose of 25 μg/mouse ClyF fully protected the mice from lethal infection. Conclusions The present data collectively showed that physiological calcium improves the bactericidal activity and host range of ClyF, making it a promising candidate for the treatment of infections caused by multiple staphylococci and streptococci.
Databáze: OpenAIRE
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