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

Imran Mohammed,Mario Nubile,Harminder S Dua,Dalia G Said,Leonardo Mastropasqua

doi:10.3389/fmicb.2019.02190

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.

Highlights

Pseudomonas aeruginosa is a ubiquitous Gram-negative bacterium, which causes opportunistic fatal infections in patients with compromised immunity (e.g., HIV, burn, cancer, and cystic fibrosis) (Poole, 2011)
LL-37 and its two derivatives, FK13 and FK16, and a range of antibiotics that are commonly used for the treatment of bacterial keratitis were tested against three different strains of Pseudomonas aeruginosa (PAO1, PA19660, and P. aeruginosa (PA-OS))
The biochemical and structural details of peptides and antibiotics was depicted in the Supplementary Table 1

Summary

Introduction

Pseudomonas aeruginosa is a ubiquitous Gram-negative bacterium, which causes opportunistic fatal infections in patients with compromised immunity (e.g., HIV, burn, cancer, and cystic fibrosis) (Poole, 2011). It is the commonest cause of bacterial keratitis in extended-use contact lens wearers. Due to its nature of the emergency, patients are mostly hospitalized requiring aggressive treatment with mono or fortified topical drops. Severe PsK cases that require surgical transplantation of donor corneal tissue are often at potential risk of graft tissue rejection (Rush and Rush, 2016). Constant paucity of transplant tissue and recent emergence of multi-drug resistant (MDR) P. aeruginosa (MDRP) has further added to the challenge to manage PsK (Willcox, 2011; Morita et al, 2014; Vazirani et al, 2015; Tuli and Gray, 2016; Chojnacki et al, 2019)

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