Abstract
The incidence of fungal infections has been increasing in the last decades, while the number of available antifungal classes remains the same. The natural and acquired resistance of some fungal species to available therapies, associated with the high toxicity of these drugs on the present scenario and makes an imperative of the search for new, more efficient and less toxic therapeutic choices. Antimicrobial peptides (AMPs) are a potential class of antimicrobial drugs consisting of evolutionarily conserved multifunctional molecules with both microbicidal and immunomodulatory properties being part of the innate immune response of diverse organisms. In this study, we evaluated 11 scorpion-venom derived non-disulfide-bridged peptides against Cryptococcus neoformans and Candida spp., which are important human pathogens. Seven of them, including two novel molecules, showed activity against both genera with minimum inhibitory concentration values ranging from 3.12 to 200 μM and an analogous activity against Candida albicans biofilms. Most of the peptides presented low hemolytic and cytotoxic activity against mammalian cells. Modifications in the primary peptide sequence, as revealed by in silico and circular dichroism analyses of the most promising peptides, underscored the importance of cationicity for their antimicrobial activity as well as the amphipathicity of these molecules and their tendency to form alpha helices. This is the first report of scorpion-derived AMPs against C. neoformans and our results underline the potential of scorpion venom as a source of antimicrobials. Further characterization of their mechanism of action, followed by molecular optimization to decrease their cytotoxicity and increase antimicrobial activity, is needed to fully clarify their real potential as antifungals.
Highlights
An increase of systemic mycoses incidence due to the rising number of immunocompromised individuals, cancer, HIV/AIDS and solid-organ transplant patients has been noticed in recent years
Different cDNAs encoding putative Antimicrobial peptides (AMPs) from the venom gland of scorpions T. obscurus, Tityus costatus, Hadrurus gertschi, and Opisthacanthus cayaporum were characterized by expressed sequence tag (EST)
The primary structures of ToAP2, ToAP1, ToAP3, ToAP4, and ToAcP peptides from T. obscurus were used as queries on BLAST
Summary
An increase of systemic mycoses incidence due to the rising number of immunocompromised individuals, cancer, HIV/AIDS and solid-organ transplant patients has been noticed in recent years. An increase in infections caused by non-albicans species has been noticed, like Candida parapsilosis, Candida tropicalis, and Candida glabrata, the latter being more resistant to antifungal drugs than other Candida species (Sobel, 2006; Pfaller and Diekema, 2007; Diekema et al, 2012; Rodrigues et al, 2014) Cryptococcus neoformans is another opportunistic pathogen of clinical relevance, especially among HIV/AIDS patients. Of particular interest is the formation of biofilms by C. albicans, which confers specialized properties to the microorganism that complicate treatment, such as the increased resistance to antimicrobial drugs and the ability to evade the host immune system, among others (Finkel and Mitchell, 2011; Fanning and Mitchell, 2012) Another problem regarding fungal infections is the rising of resistance to currently available antifungal drugs (Pan et al, 2012; Pfaller, 2012; Arendrup, 2013). This is compounded by the intrinsic resistance of some fungi to antifungals, such as C. neoformans to echinocandins and C. glabrata to azoles (Sable et al, 2008; Pfaller, 2012; Paul and Moye-Rowley, 2014)
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