Antimicrobial Activity and Cell Selectivity of Synthetic and Biosynthetic Cationic Polymers.

Mayandi Venkatesh,Rajamani Lakshminarayanan,Navin Kumar Verma,Mobashar Hussain Urf Turabe Fazil,Veluchamy Amutha Barathi,Raditya Anggara,Thet Tun Aung,Stephen John Fox,Xian Jun Loh,Shouping Liu,Eunice Tze Leng Goh,Liang Yang,Timothy Mark Sebastian Barkham,Roger W Beuerman,Alice Jie Ying Ng,Sriram Harini

doi:10.1128/aac.00469-17

Abstract

ABSTRACTThe mammalian and microbial cell selectivity of synthetic and biosynthetic cationic polymers has been investigated. Among the polymers with peptide backbones, polymers containing amino side chains display greater antimicrobial activity than those with guanidine side chains, whereas ethylenimines display superior activity over allylamines. The biosynthetic polymer ε-polylysine (εPL) is noncytotoxic to primary human dermal fibroblasts at concentrations of up to 2,000 μg/ml, suggesting that the presence of an isopeptide backbone has greater cell selectivity than the presence of α-peptide backbones. Both εPL and linear polyethylenimine (LPEI) exhibit bactericidal properties by depolarizing the cytoplasmic membrane and disrupt preformed biofilms. εPL displays broad-spectrum antimicrobial properties against antibiotic-resistant Gram-negative and Gram-positive strains and fungi. εPL elicits rapid bactericidal activity against both Gram-negative and Gram-positive bacteria, and its biocompatibility index is superior to those of cationic antiseptic agents and LPEI. εPL does not interfere with the wound closure of injured rabbit corneas. In a rabbit model of bacterial keratitis, the topical application of εPL (0.3%, wt/vol) decreases the bacterial burden and severity of infections caused by Pseudomonas aeruginosa and Staphylococcus aureus strains. In vivo imaging studies confirm that εPL-treated corneas appeared transparent and nonedematous compared to untreated infected corneas. Taken together, our results highlight the potential of εPL in resolving topical microbial infections.

Highlights

Anti-Infectives Research Group, Singapore Eye Research Institute, The Academia, Singaporea; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Graduate Medical School, Singaporeb; Lee Kong
The rapid upsurge in the evolution of antibiotic-resistant bacteria undermines the antibiotic armamentarium and endangers the benefits achieved with antibiotics
Recent studies showed that cationic antimicrobial polymers are potent alternatives for combating drug-resistant pathogens, owing to their rapid bactericidal and membranetargeting actions

Summary

Introduction

Anti-Infectives Research Group, Singapore Eye Research Institute, The Academia, Singaporea; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Graduate Medical School, Singaporeb; Lee Kong. Antiseptics are antimicrobial agents that can rapidly inhibit or destroy the growth of microorganisms and are an important component of infection control and prevention in hospitals and health care settings [1,2,3]. Their broad-spectrum antimicrobial activity, rapid inhibitory or microbicidal activity, and nonspecific mode of action potentially slow the evolution of antimicrobial resistance. The biosynthetic polymer ␧-polylysine (␧PL) is noncytotoxic to primary human dermal fibroblasts at concentrations of up to 2,000 ␮g/ml, suggesting that the presence of an isopeptide backbone has greater cell selectivity than the presence of ␣-peptide backbones Both ␧PL and linear polyethylenimine (LPEI) exhibit bactericidal properties by depolarizing the cytoplasmic membrane and disrupt preformed biofilms. Both ␧PL and linear polyethylenimine (LPEI) exhibit bactericidal properties by depolarizing the cytoplasmic membrane and disrupt preformed biofilms. ␧PL displays broad-spectrum antimicrobial properties against antibiotic-resistant

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