Assessment of Apolipoprotein E Derived Peptides as Novel Antimicrobials for the Coating of Biomedical Devices

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Abstract

The microbial contamination of biomedical devices is a leading cause of hospital- acquired infection. A number of strategies aimed at developing device coatings that are refractory to microbial adhesion, colonisation and biofilm formation have been developed, but the problem remains. The incorporation of biocides into biomedical device surface coatings has shown promising results in preventing the establishment of infection. Current controversy over the possibility that extensive use of biocides could potentially lead to antimicrobial resistance has fuelled the search for new actives with good antimicrobial activity and low cytotoxicity, that maintain marked efficacy after prolonged use. This doctoral thesis aims to evaluate the antimicrobial potential of a novel peptide based on human apolipoprotein E receptor binding region (apoEdpL-W). The spectrum of antimicrobial activity and anti-biofilm efficacy of apoEdpL-W was compared to that of common biocides polyhexamethylene biguanide, triclosan, cetrimide and chlorhexidine. The potential to induce bacterial insusceptibility towards these agents after long-term sub-lethal level exposure was assessed. Initial examination against 18 test microorganisms, commonly associated with device infection, showed that apoEdpL-W displayed broad-range antimicrobial and anti-biofilm efficacy. ApoEdpL-W also maintained marked antibacterial activity after incorporation onto various biomaterial polymers, often used in device surface coatings. Alterations in bacterial susceptibility after prolonged exposure to apoEdpL-W, as well as to the other biocides, were often temporary and partially reverted once the bacteria had been grown in the absence of the antimicrobial agent. The adaption of Staphylococcus aureus to the presence of triclosan resulted in the formation of small colony variants (SVCs) with reduced triclosan susceptibility. Analysis of the physiological characteristics of the triclosan induced SCVs revealed the loss of virulence determinants and potentially reduced pathogenic capability, when compared to the parent strain. The biocompatibility index values of the test actives were determined by the parallel assessment of their antibacterial activity and in vitro cytotoxicity. ApoEdpL-W showed good antibacterial efficacy whilst remaining relatively less toxic to mammalian cells than triclosan or chlorhexidine. We studied the interactions of the test antimicrobials with a preformed phospholipid bilayer using the quartz crystal microbalance device and dual polarisation interferometry, to better understand potential mode of action. Analysis revealed that ApoEdpL-W and PHMB induced the highest level of bilayer disruption, of all the antimicrobials tested. These data suggest that apoEdpL-W demonstrates antibacterial activity; biocompatibility and long-term efficacy on a level that compares favourably to that of currently used biocides. The peptide demonstrates good antimicrobial efficacy when incorporated into a range of biomaterial polymers and shows the potential to be developed as an effective coating for the reduction of device associated infections.

Keyword(s)

Antimicrobial peptide; Biocide; Medical device

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