The Engineered Lysin CF-370 Is Active Against Antibiotic-Resistant Gram-Negative Pathogens In Vitro and Synergizes With Meropenem in Experimental Pseudomonas aeruginosa Pneumonia.
J Infect Dis
; 230(2): 309-318, 2024 Aug 16.
Article
in En
| MEDLINE
| ID: mdl-38366561
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pseudomonas aeruginosa
/
Pseudomonas Infections
/
Microbial Sensitivity Tests
/
Pneumonia, Bacterial
/
Drug Synergism
/
Meropenem
/
Anti-Bacterial Agents
Limits:
Animals
Language:
En
Journal:
J Infect Dis
/
J. infect. dis
/
Journal of infectious diseases
Year:
2024
Document type:
Article
Country of publication:
Estados Unidos