PDF(Pubmed)
Abstract：
BACKGROUND: 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 the engineered lysin CF-370 was examined in vitro and in vivo against gram-negative pathogens important in human infections.
METHODS: Minimum inhibitory concentration (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.
RESULTS: 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 bactericidal activity, activity in serum, a low propensity for resistance, anti-biofilm activity, and synergy with antibiotics. In the pneumonia model, CF-370 alone decreased bacterial densities in lungs, kidneys, and spleen versus vehicle control, and demonstrated significantly increased efficacy when combined with meropenem (vs either agent alone).
CONCLUSIONS: 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 multisystem infection.
METHODS: Minimum inhibitory concentration (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.
RESULTS: 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 bactericidal activity, activity in serum, a low propensity for resistance, anti-biofilm activity, and synergy with antibiotics. In the pneumonia model, CF-370 alone decreased bacterial densities in lungs, kidneys, and spleen versus vehicle control, and demonstrated significantly increased efficacy when combined with meropenem (vs either agent alone).
CONCLUSIONS: 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 multisystem infection.
摘要：
背景:靶向革兰氏阴性生物体的溶素(细胞壁水解酶)需要工程改造以透化外膜并进入下面的肽聚糖以促进杀伤。在目前的研究中,工程溶素的潜在临床用途，在体外和体内检查了CF-370对人类感染中重要的革兰氏阴性病原体。
方法:使用标准方法测定MIC和杀菌活性。使用由铜绿假单胞菌引起的兔急性肺炎模型进行体内概念验证功效研究。
结果：CF-370表现出有效的抗菌活性，MIC50/90值（以µg/mL为单位）：铜绿假单胞菌，1/2;鲍曼不动杆菌,1/1;大肠杆菌，0.25/1;肺炎克雷伯菌，2/4；阴沟肠杆菌1/4；嗜麦芽窄食单胞菌2/8。CF-370还证明:i)杀菌活性;(ii)在血清中的活性;iii)低抗性倾向;iv)抗生物膜活性;和v)与抗生素的协同作用。在肺炎模型中,单独的CF-370降低了肺部的细菌密度，肾和脾vs.车辆控制,与美罗培南联合使用时，疗效显着提高（与单独使用任何一种药物相比）。
结论：CF-370是第一个被描述为具有针对多种临床相关革兰氏阴性病原体的有效广谱体外活性的工程溶素，以及在严重侵入性多系统感染的动物模型中的有效体内功效。
方法:使用标准方法测定MIC和杀菌活性。使用由铜绿假单胞菌引起的兔急性肺炎模型进行体内概念验证功效研究。
结果：CF-370表现出有效的抗菌活性，MIC50/90值（以µg/mL为单位）：铜绿假单胞菌，1/2;鲍曼不动杆菌,1/1;大肠杆菌，0.25/1;肺炎克雷伯菌，2/4；阴沟肠杆菌1/4；嗜麦芽窄食单胞菌2/8。CF-370还证明:i)杀菌活性;(ii)在血清中的活性;iii)低抗性倾向;iv)抗生物膜活性;和v)与抗生素的协同作用。在肺炎模型中,单独的CF-370降低了肺部的细菌密度，肾和脾vs.车辆控制,与美罗培南联合使用时，疗效显着提高（与单独使用任何一种药物相比）。
结论：CF-370是第一个被描述为具有针对多种临床相关革兰氏阴性病原体的有效广谱体外活性的工程溶素，以及在严重侵入性多系统感染的动物模型中的有效体内功效。
