Development of a novel hybrid antimicrobial peptide for targeted killing of Pseudomonas aeruginosa

• Published in: European journal of medicinal chemistry Vol. 185; p. 111814
• Main Authors: Kim, Hyun, Jang, Ju Hye, Kim, Sun Chang, Cho, Ju Hyun
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.01.2020
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antimicrobial Cationic Peptides - chemical synthesis; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial peptide; Dose-Response Relationship, Drug; Female; Hybrid peptide; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Multidrug-resistant Pseudomonas aeruginosa; OprF; Pseudomonas aeruginosa - cytology; Pseudomonas aeruginosa - drug effects; Pseudomonas Infections - drug therapy; Selective antimicrobial activity; Structure-Activity Relationship; OprF; Hybrid peptide; Selective antimicrobial activity; Antimicrobial peptide; Multidrug-resistant Pseudomonas aeruginosa
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111814

The emergence of multidrug-resistant (MDR) Pseudomonas aeruginosa, coupled with shrinking antibiotic pipelines, has increased the demand for new antimicrobials with novel mechanisms of action. As the indiscriminate nature of broad-spectrum antimicrobial toxicity may have negative clinical consequences and increase the incidence of resistance, we have developed a P. aeruginosa-selective antimicrobial peptide capable of preferentially killing P. aeruginosa relative to benign microorganisms. A targeting peptide (PA2) that binds specifically to OprF porin on P. aeruginosa was identified by phage display peptide library screening, and a hybrid peptide was constructed by addition of the targeting peptide to GNU7, a potent antimicrobial peptide. The resulting hybrid peptide PA2-GNU7 exhibited potent antimicrobial activity against P. aeruginosa without causing host toxicity. Confocal laser scanning microscopy analysis and time-kill experiments demonstrated that PA2-GNU7 exhibited a high degree of specificity for P. aeruginosa, and rapidly and selectively killed P. aeruginosa cells in mixed cultures. In addition, in vivo treatment efficacy of PA2-GNU7 was significantly greater than that of conventional antibiotics in a mouse model of MDR P. aeruginosa infection. Taken together, the data suggest that PA2-GNU7 may be a promising template for further development as a novel anti-MDR P. aeruginosa therapeutic agent. [Display omitted] •P. aeruginosa targeting peptide (PA2) was identified by phage display screening.•Hybrid peptide (PA2-GNU7) was constructed by addition of PA2 to GNU7, an AMP.•PA2-GNU7 exhibited high specificity for P. aeruginosa through binding to OprF.•PA2-GNU7 rapidly and selectively killed P. aeruginosa cells in mixed cultures.•In vivo therapeutic efficacy of PA2-GNU7 was greater than that of meropenem.