Cationic amphiphilic alpha-helical peptides for the treatment of carbapenem-resistant Acinetobacter baumannii infection

Abstract

The emergence of multidrug-resistant Gram-negative bacteria, in particular Acinetobacter baumannii and Pseudomonas aeruginosa, is a critical clinical problem worldwide. Antimicrobial peptides (AMPs) have received increasing attention due to their ability to overcome multidrug-resistant microbes. We recently reported that cysteine-functionalized alpha-helical peptides LLKKLLKKC and CLLKKLLKKC effectively eradicated Gram-negative bacteria in vitro. In this study, the antibacterial properties of these peptides against carbapenem-resistant clinical isolates of A. baumannii were studied both in vitro and in vivo. The minimum inhibitory concentrations (MICs) of the peptides against 20 clinical isolates of carbapenem-resistant A. baumannii were determined in comparison with imipenem. The results showed that the A. baumannii isolates were more susceptible to (LLKK)2C than to C(LLKK)2C in vitro, and 90% of the 20 tested strains had an MIC of lower than or equal to 36.8 and 63.1 μmol/L, respectively. However, the bactericidal effect of C(LLKK)2C was much faster than that of (LLKK)2C. Furthermore, these peptides also showed excellent potency in mouse models of peritonitis and pneumonia infections caused by carbapenem-resistant A. baumannii. Importantly, both peptides had a high therapeutic index (>25), but caused no significant adverse effects on the liver and kidney functions and the balance of electrolytes in the blood. These peptides can be a promising alternative treatment modality to traditional antibiotics for nosocomial bacterial infections caused by multidrug-resistant Gram-negative bacteria, especially carbapenem-resistant A. baumannii.