The Engineered Lysin CF-370 is Active Against Antibiotic-Resistant Gram-Negative Pathogens in Vitro and Synergizes with Meropenem in Experimental Pseudomonas Aeruginosa Pneumonia

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 mu g/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. Engineered lysin CF-370, which demonstrated broad-spectrum in vitro activity against multiple clinically relevant gram-negative pathogens and in vivo efficacy in an animal model of invasive multisystem infection, showed therapeutic potential as systemic treatment for infections with antibiotic-resistant pathogens.