title: 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)(2)C than to C(LLKK)(2)C 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)(2)C was much faster than that of (LLKK)(2)C. 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.
authors.affiliation: Program of Innovative Therapeutics, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou 310003, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
authors.forename: Nikken
authors.initials: N
authors.lastname: Wiradharma
authors.forename: Kaijin
authors.initials: K
authors.lastname: Xu
authors.forename: Zhongkang
authors.initials: Z
authors.lastname: Ji
authors.forename: Sheng
authors.initials: S
authors.lastname: Bi
authors.forename: Lanjuan
authors.initials: L
authors.lastname: Li
authors.forename: Yi-Yan
authors.initials: YY
authors.lastname: Yang
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D015780:Carbapenems / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D006801:Humans; D007928:Lethal Dose 50; D008168:Lung / Q000382:microbiology; D008297:Male; D051379:Mice; D010537:Peritoneum / Q000382:microbiology; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D015780:Carbapenems