Abstract
Candida albicans is a polymorphic fungus responsible for mucosal and skin infections. Candida cells establish themselves into biofilm communities resistant to most currently available antifungal agents. An increase of severe infections ensuing in fungal septic shock in elderly or immunosuppressed patients, along with the emergence of drug-resistant strains, urge the need for the development of alternative antifungal agents. In the search for novel antifungal drugs our laboratory demonstrated that two human ribonucleases from the vertebrate-specific RNaseA superfamily, hRNase3 and hRNase7, display a high anticandidal activity. In a previous work, we proved that the N-terminal region of the RNases was sufficient to reproduce most of the parental protein bactericidal activity. Next, we explored their potency against a fungal pathogen. Here, we have tested the N-terminal derived peptides that correspond to the eight human canonical RNases (RN1-8) against planktonic cells and biofilms of C. albicans. RN3 and RN7 peptides displayed the most potent inhibitory effect with a mechanism of action characterized by cell-wall binding, membrane permeabilization and biofilm eradication activities. Both peptides are able to eradicate planktonic and sessile cells, and to alter their gene expression, reinforcing its role as a lead candidate to develop novel antifungal and antibiofilm therapies.
Highlights
Candida albicans is the most common fungal pathogen that threatens hospitalized and immunocompromised patients
In the search for novel antifungal agents, we recently reported that human antimicrobial RNases are effective against C. albicans through a dual mode of action [21,22]
The eight N-terminal peptides (RN1–8), comprising equivalent structural regions of the human canonical RNases N-termini [residues 1–45 of hRNases 2, 6, 7 and 8; residues 1–48 of hRNases 1 and 4; and residues 1–47 of hRNase 5;] were selected for synthesis to test their antimicrobial capabilities against C. albicans
Summary
Candida albicans is the most common fungal pathogen that threatens hospitalized and immunocompromised patients. Distributed throughout the different organism tissues, AMPs play an essential role as part of the human innate immune system, constantly protecting the body against microbial invasion and diseases [6,7,8] Because of their wide distribution, physicochemical features, biological activities and rapid antimicrobial action against a broad spectrum of microbes, AMPs have recently attracted significant attention as encouraging antibiotic candidates [9,10,11,12,13]. Due to their direct action at the microbial membrane and multifaceted intracellular killing mechanisms, the use of AMPs as antibiotics should reduce the appearance of resistant pathogens, a scenario that has been favored by the abuse of conventional antibiotics [14,15]. Among the human peptides that participate in the host innate immunity against fungal infections, we find cathelicidins, histatins and defensins, that combine direct action to the pathogen cell together with indirect immune-modulation activities [17]
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