铜绿假单胞菌
美罗培南
微生物学
鲍曼不动杆菌
嗜麦芽窄食单胞菌
抗生素
阴沟肠杆菌
体内
肺炎克雷伯菌
抗菌剂
产气肠杆菌
生物
抗生素耐药性
细菌
大肠杆菌
遗传学
生物化学
基因
生物技术
作者
Karen Sauve,Aubrey Watson,Jun Kyun Oh,Steven M. Swift,Xavier Vila‐Farrés,Wessam Abdelhady,Yan Xiong,Dario Lehoux,Gary Woodnutt,Arnold S. Bayer,Raymond Schuch
标识
DOI:10.1093/infdis/jiae027
摘要
Lysins (cell wall hydrolases) targeting Gram-negative organisms require engineering to permeabilize the outer membrane and access subjacent peptidoglycan to facilitate killing. In the current study, the potential clinical utility for engineered lysin, CF-370, was examined in vitro and in vivo against Gram-negative pathogens important in human infections.MICs and bactericidal activity were determined using standard methods. An in vivo proof-of-concept efficacy study was conducted using a rabbit acute pneumonia model caused by Pseudomonas aeruginosa.CF-370 exhibited potent antimicrobial activity, with MIC50/90 values (in µg/mL) for: P. aeruginosa, 1/2; Acinetobacter baumannii, 1/1; Escherichia coli, 0.25/1; Klebsiella pneumoniae, 2/4; Enterobacter cloacae 1/4; and Stenotrophomonas maltophilia 2/8. CF-370 furthermore demonstrated: i) bactericidal activity; (ii) activity in serum; iii) a low propensity for resistance; iv) anti-biofilm activity; and v) synergy with antibiotics. In the pneumonia model, CF-370 alone decreased bacterial densities in lungs, kidneys and spleen vs. vehicle control, and demonstrated significantly increased efficacy when combined with meropenem (vs either agent alone).CF-370 is the first engineered lysin described with potent broad spectrum in vitro activity against multiple clinically-relevant Gram-negative pathogens, as well as potent in vivo efficacy in an animal model of severe invasive multi-system infection.
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