Cathelicidin-Derived Synthetic Peptide Improves Therapeutic Potential of Vancomycin Against Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa (PA) is the leading cause of corneal blindness worldwide. A constant increase in multi-drug resistant PA strains have heightened the challenge of effectively managing corneal infections with conventional antibiotics. Antimicrobial peptides are promising antibiotic analogs with a unique mode of action. Cathelicidin-derived shorter peptides (FK13 and FK16) have previously been shown to kill a range of pathogens in both in vitro and in vivo systems. Here, our aim was to exploit the potential of FK13 or FK16 to enhance the anti-Pseudomonas activity of vancomycin, which normally has low clinical efficacy against PA. Our results have demonstrated that FK16 is more potent than FK13 against different PA strains including a clinical isolate from a patient’s ocular surface. FK16 was shown to enhance the membrane permeability of PAO1 at sub-inhibitory concentrations. Moreover, FK16 at lower concentrations was shown to increase the antibacterial susceptibility of vancomycin against PA strains up to eightfold. The bactericidal synergism between FK16 and vancomycin was shown to be stable in the presence of physiological tear salt concentration and did not cause toxic effects on the human corneal epithelial cells and human red blood cells. Our results have revealed that sub-inhibitory concentration of FK16 could augment the antimicrobial effects of vancomycin against PA. It is anticipated that the future exploitation of the peptide design approach may enhance the effectiveness of FK16 and its application as an adjuvant to antibiotic therapy for the treatment of multi-drug resistant infections.

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

“…Hybridization of this tag sequence to a membrane-lytic short peptide, GNU-7, was shown to improve the antimicrobial efficacy of parent GNU-7 by 16-fold toward P. aeruginosa both in in vitro and in vivo model systems. LPS-targeting GNU-7 variants were also developed through hybridization with lactoferrin (28-34), BPI (84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99), and de novo sequence (125). Chimeric bactericidal peptides targeted to E. faecalis (123) and S. mutans (124) were also developed based on the species-specific pheromones.…”

“…There are also increasing reports examining and exploiting the strategy of using peptide-antibiotic combination to counter AMR, increase the lifespan of conventional antibiotics and HDPs, as well as to reduce the undesired toxicity to host tissues (88,(192)(193)(194). The synergistic effect of peptide-antibiotic combination treatment is likely attributed to the different underlying mechanism of action whereby the membrane perturbation effect of peptides facilitates the passive diffusion of conventional antibiotics into the cells for intracellular targeting action (192).…”

“…Wang et al (77), Mishra and Wang (87) have recently demonstrated that titanium surface immobilized FK-16 (a short variant of LL-37) is highly antimicrobial against ESKAPE pathogens. Our group has recently demonstrated that FK-16 could be used for repurposing conventional antibiotics such as vancomycin as a strategy to counter antimicrobial resistance (88). Further improvement of FK-16 by Narayana et al (89) have also led to the development of GF-17, 17BIPHE2, and other related variants of superior efficacy and safety compared to LL-37.…”

Shorter Antibacterial Peptide Having High Selectivity for E. coli Membranes and Low Potential for Inducing Resistance

“…Although many peptides isolated from natural sources have powerful antimicrobial activity, they frequently have certain limitations related to their toxicity against mammalian cells, high production costs and poor stability and/or bioavailability in host physiological conditions [ 14 , 15 ]; synthetic peptides have thus aroused interest. In addition to isolating natural AMPs [ 16 ], synthetic AMPs can be obtained by recombinant expression [ 17 ] or chemical synthesis [ 18 ]; the latter has become popular due to its advantages such as extremely pure products being able to be obtained rapidly and efficiently [ 19 ].…”

Effects of human β-defensin 3 fused with carbohydrate-binding domain on the function of type III secretion system in Pseudomonas aeruginosa PA14

“…At the same time, P. aeruginosa can also form a biofilm, which makes it more difficult to find an effective treatment [6]. Several studies have confirmed that AMPs have killing effects on P. aeruginosa and its biofilm, and may assist in the treatment of antibiotics [8,9]. We have reported the bactericidal effects against P. aeruginosa PA14 (PA14) of hBD3-CBD with in vitro bactericidal test, individual gene expressions, biofilm formation assays, swimming, twitching, and swarming activities [7].…”