Antimicrobial Photodynamic therapy enhanced by the peptide aurein 1.2

Laura Marise De Freitas,Esteban Nicolás Lorenzón,Kleber Thiago De Oliveira,Marciana Pierina Uliana,Carla Raquel Fontana,Lucas Henrique De Paula Zago,Eduardo Maffud Cilli,Norival Alves Santos-Filho

doi:10.1038/s41598-018-22687-x

Abstract

In the past few years, the World Health Organization has been warning that the post-antibiotic era is an increasingly real threat. The rising and disseminated resistance to antibiotics made mandatory the search for new drugs and/or alternative therapies that are able to eliminate resistant microorganisms and impair the development of new forms of resistance. In this context, antimicrobial photodynamic therapy (aPDT) and helical cationic antimicrobial peptides (AMP) are highlighted for the treatment of localized infections. This study aimed to combine the AMP aurein 1.2 to aPDT using Enterococcus faecalis as a model strain. Our results demonstrate that the combination of aPDT with aurein 1.2 proved to be a feasible alternative capable of completely eliminating E. faecalis employing low concentrations of both PS and AMP, in comparison with the individual therapies. Aurein 1.2 is capable of enhancing the aPDT activity whenever mediated by methylene blue or chlorin-e6, but not by curcumin, revealing a PS-dependent mechanism. The combined treatment was also effective against different strains; noteworthy, it completely eliminated a vancomycin-resistant strain of Enterococcus faecium. Our results suggest that this combined protocol must be exploited for clinical applications in localized infections as an alternative to antibiotics.

Highlights

In the past few years, the World Health Organization has been warning that the post-antibiotic era is an increasingly real threat
This inference is based on the principle that the binding of molecules to a lipid bilayer alters its physical properties, changing both its thickness and elasticity[43], and is in accordance with the data obtained by Vermathen et al.[44], whose study demonstrate that the higher the degree of aggregation of Ce6, the lower its internalization, and the data from Fuchs et al.[45], which demonstrate that higher membrane instability makes the cells more susceptible to antimicrobial photodynamic therapy (aPDT)
The combination of aPDT with the antimicrobial peptides (AMP) aurein 1.2 proved to be a feasible alternative to conventional antimicrobial agents to potentially overcome bacterial resistance, capable of eliminating two of the most resistant strains responsible for community and nosocomial infections, E. faecalis and E. faecium, and significantly reduce the viability of S. aureus, A. baumannii and E. coli

Summary

Introduction

In the past few years, the World Health Organization has been warning that the post-antibiotic era is an increasingly real threat. The local application of aPDT avoids systemic adverse effects, it usually requires high concentrations of photosensitizers and high-energy doses of light to completely eliminate infectious bacteria, in the cases of persistent infections, which can lead to harm of host cells, impairing local immune response and tissue healing[8], and even leading to tissue necrosis[12,13]. To overcome such a drawback, aPDT can be combined with other agents or drugs, improving the overall result while reducing individual concentrations and avoiding host tissue damaging[14,15,16]. In addition to a possible loss of activity of both molecules due to the conformational changes caused by the conjugation, AMPs present an important antimicrobial activity by themselves to be used as a simple targeting

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