A Novel Dual-Targeted α-Helical Peptide With Potent Antifungal Activity Against Fluconazole-Resistant Candida albicans Clinical Isolates

Abstract

Due to compromised immune system, fungal infection incidences have markedly increased in the last few decades. Pathogenic fungi have developed resistance to the clinically available antifungal agents. Antifungal resistance poses a great challenge to clinical treatment and has stimulated the demand for novel antifungal agents. A promising alternative to the treatment of fungal diseases is the use of antimicrobial peptides (AMPs). However, the antifungal activities of AMPs have not been fully determined. Therefore, this study aimed at designing and screening α-helical peptides with potential antifungal activities. The effects of key physicochemical parameters on antifungal activities were also investigated. A series of lengthened and residue-substituted derivatives of the template peptide KV, a hexapeptide truncated from the α-helical region of porcine myeloid antimicrobial peptide-36, were designed and synthesized. Enhancement of hydrophobicity by introducing aromatic hydrophobic amino acids (tryptophan and phenylalanine) significantly increased the efficacies of the peptides against Candida albicans strains, including fluconazole-resistant isolates. Increased hydrophobicity also elevated the toxic properties of these peptides. RF3 with moderate hydrophobicity exhibited potent anticandidal activities (GM = 6.96 μM) and modest hemolytic activities (HC10 > 64 μM). Additionally, repeated exposure to a subinhibitory concentration of RF3 did not induce resistance development. The antifungal mechanisms of RF3 were due to membrane disruptions and induction of reactive oxygen species production. Such a dual-targeted mechanism was active against drug-resistant fungi. These results show the important role of hydrophobicity and provide new insights into designing and developing antifungal peptides. Meanwhile, the successful design of RF3 highlights the potential utility of AMPs in preventing the spread of drug-resistant fungal infections.

Potent Antimicrobial and Antibiofilm Activities of Feleucin-K3 Analogs Modified by α-(4-Pentenyl)-Ala against Multidrug-Resistant Bacteria

“…These polymers might act to trap the AMPs, facilitating the penetration of the cell wall [42]. Subsequently, the outer membrane permeability and cytoplasmic membrane depolarization induced by K65 and K70 rapidly increased and had significant time-and concentration-dependent effects, indicating that the peptide-membrane interaction might be related to channel or pore formation, thus leading to cellular component leakage and cell death [43]. Interestingly, depolarization of the S. aureus cytoplasmic membrane induced by the Feleucin-K3 analogs was weaker than that in Gram-negative bacteria.…”

Antifungal Combination of Ethyl Acetate Extract of Poincianella pluviosa (DC.) L. P. Queiros Stem Bark With Amphotericin B in Cryptococcus neoformans

“…Moreover, as described above, hydrolyzable tannins (Bueno et al, 2014) such as pyrogallol, ellagic acid, and gallic acid (Sereia et al, 2019) were identified in the EAF from P. pluviosa stem bark. The antifungal activity of all these compounds has already been described for different species of fungi (de Paula E Silva et al, 2014;Yang et al, 2020); besides, the immunomodulatory activity of polyphenols was also well-known (Ding et al, 2018). Particularly, gallic acid inhibits the growth of C. neoformans (de Paula E Silva et al, 2014) and can modulate the host innate immune response, increasing defense against microbial infections (Yang et al, 2020).…”

“…The antifungal activity of all these compounds has already been described for different species of fungi (de Paula E Silva et al, 2014;Yang et al, 2020); besides, the immunomodulatory activity of polyphenols was also well-known (Ding et al, 2018). Particularly, gallic acid inhibits the growth of C. neoformans (de Paula E Silva et al, 2014) and can modulate the host innate immune response, increasing defense against microbial infections (Yang et al, 2020). Therefore, the combined antivirulence and immunomodulatory activities of the polyphenols may be responsible for the therapeutic effect of EAF from P. pluviosa stem bark observed in G. mellonella infection in the present study.…”

In vitro Antifungal Activity of a Novel Antimicrobial Peptide AMP-17 Against Planktonic Cells and Biofilms of Cryptococcus neoformans

“…The effect of AMP-17 on membrane permeability was detected by flow cytometry, according to a previously described method, with minor modifications. 31 Briefly, C. neoformans cells were diluted to 1.0×10 6 CFU/mL. Cell suspensions were incubated for 6 h at 35 °C with 1, 2, and 4× MIC AMP-17.…”