Abstract
The threat of antimicrobial resistance to society is compounded by a relative lack of new clinically effective licensed therapies reaching patients over the past three decades. This has been particularly problematic within antifungal drug development, leading to a rise in fungal infection rates and associated mortality. This paper highlights the potential of an ultrashort peptide, (naphthalene-2-ly)-acetyl-diphenylalanine-dilysine-OH (NapFFKK-OH), encompassing hydrogel-forming and antifungal properties within a single peptide motif, thus overcoming formulation (e.g., solubility, drug loading) issues associated with many currently employed highly hydrophobic antifungals. A range of fungal susceptibility (colony counts) and cell cytotoxicity (MTS cell viability, LIVE/DEAD staining® with fluorescent microscopy, haemolysis) assays were employed. Scanning electron microscopy confirmed the nanofibrous architecture of our self-assembling peptide, existing as a hydrogel at concentrations of 1% w/v and above. Broad-spectrum activity was demonstrated against a range of fungi clinically relevant to infection (Aspergillus niger, Candida glabrata, Candida albicans, Candida parapsilosis and Candida dubliniensis) with greater than 4 log10 CFU/mL reduction at concentrations of 0.5% w/v and above. We hypothesise antifungal activity is due to targeting of anionic components present within fungal cell membranes resulting in membrane disruption and cell lysis. NapFFKK-OH demonstrated reduced toxicity against mammalian cells (NCTC 929, ARPE-19) suggesting increased selectivity for fungal cells. However, further studies relating to safety for systemic administration is required, given the challenges toxicity has presented in the wider context of antimicrobial peptide drug development. Overall this study highlights the promise of NapFFKK-OH hydrogels, particularly as a topical formulation for the treatment of fungal infections relating to the skin and eyes, or as a hydrogel coating for the prevention of biomaterial related infection.
Highlights
IntroductionOveruse of and bacterial resistance to antibiotics receives the majority of public attention; the emergence of fungi resistant to multiple therapies has led to an urgent need for new, effective and safe antifungal agents [1]
Antimicrobial resistance is a severe and increasing threat to society
Scanning electron microscopy (SEM) images (Figure 2) confirmed NapFFKK-OH hydrogels were of nanofibrous architecture despite the presence of some drying artefacts due to flash freezing of the hydrogel formulation
Summary
Overuse of and bacterial resistance to antibiotics receives the majority of public attention; the emergence of fungi resistant to multiple therapies has led to an urgent need for new, effective and safe antifungal agents [1]. The incidences of fungal infection are increasing due to factors such as an ageing population, increasing the prevalence of underlying disease (AIDS, cancer, diabetes) [2]. Modern medicine has contributed to an increase in fungal infections directly through the use of medical devices (e.g., catheters), immunosuppressive therapies and antibiotics [3,4]. Gels 2018, 4, 48 the two most common forms of fungal disease [5]. If the normal microflora is disturbed, for example due to use of antibiotics, it becomes an opportunistic pathogen [6].
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