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- Title
The Engineered Lysin CF-370 Is Active Against Antibiotic-Resistant Gram-Negative Pathogens In Vitro and Synergizes With Meropenem in Experimental Pseudomonas aeruginosa Pneumonia.
- Authors
Sauve, Karen; Watson, Aubrey; Oh, Jun T; Swift, Steven; Vila-Farres, Xavier; Abdelhady, Wessam; Xiong, Yan Q; LeHoux, Dario; Woodnutt, Gary; Bayer, Arnold S; Schuch, Raymond
- 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.
- Subjects
GRAM-negative bacteria; STENOTROPHOMONAS maltophilia; ACINETOBACTER baumannii; KLEBSIELLA pneumoniae; PSEUDOMONAS aeruginosa
- Publication
Journal of Infectious Diseases, 2024, Vol 230, Issue 2, p309
- ISSN
0022-1899
- Publication type
Article
- DOI
10.1093/infdis/jiae027