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Development of a novel hybrid antimicrobial peptide for targeted killing of Pseudomonas aeruginosa
- Source :
- European Journal of Medicinal Chemistry. 185:111814
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- 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.
- Subjects :
- medicine.drug_class
Antibiotics
Peptide
Microbial Sensitivity Tests
medicine.disease_cause
01 natural sciences
Microbiology
Mice
Structure-Activity Relationship
03 medical and health sciences
Drug Discovery
medicine
Animals
Pseudomonas Infections
Gene
030304 developmental biology
Pharmacology
chemistry.chemical_classification
Mice, Inbred BALB C
0303 health sciences
Dose-Response Relationship, Drug
010405 organic chemistry
Pseudomonas aeruginosa
Organic Chemistry
General Medicine
Antimicrobial
Treatment efficacy
Anti-Bacterial Agents
0104 chemical sciences
chemistry
Toxicity
Porin
Female
Antimicrobial Cationic Peptides
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 185
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....278147656d9af28c13275ac927ec23a1