Abstract
Increases in the numbers of immunocompromised patients and the emergence of drug-resistance fungal pathogens have led to the need for new, safe, efficacious antifungal agents. In this study, we designed a histidine-lysine-lysine (HKK) motif and synthesized six HKK peptides with repetitions of the motif. These peptides showed length-dependent antifungal activity against drug-susceptible and drug-resistant fungal pathogens via membranolytic or non-membranolytic action. None of the peptides were cytotoxic to rat erythrocytes or NIH3T3 mouse embryonic fibroblasts. Short-length peptides were directly translocated in fungal cytosol and reacted with mitochondria, resulting in apoptosis. Membrane-permeabilizing activity occurred in the presence of long peptides, and peptides were able to transfer to the cytosol and induce reactive oxygen species. Our results suggest that peptides composed only of cationic amino acids may be good candidates as antifungal agents.
Highlights
The incidence and diversity of invasive fungal infections are growing, and fungal pathogens are a global threat to public health
In this study we aimed to develop a novel antifungal agent based on an antifungal histone-lysine-lysine (HKK) motif, which consisted of only two hydrophilic amino acids, histidine and lysine, and showed antifungal activity
The environmental pH of tissues and cells infected by fungal pathogens can be altered from 4 to 7.5 within a few hours; in particular, Candida albicans induces an acidified environment to express virulence and pathogenesis [13,14]
Summary
The incidence and diversity of invasive fungal infections are growing, and fungal pathogens are a global threat to public health. This is so in immunocompromised patients with human immunodeficiency virus/acquired immunodeficiency syndrome or cancer [1,2]. The existing antibiotic agents that act against fungi, such as flucytosine and azole agents, are ineffective because of the appearance of multidrug-resistant strains. Promising candidates include antimicrobial peptides (AMPs) isolated from diverse sources such as plants, bacteria, fungi, and animals [4]. AMPs have a selective targeting ability in pathogens and multiple modes of action, offering less opportunity for the development of resistance [5]
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