Synergistic Activity of the N-Terminal Peptide of Human Lactoferrin and Fluconazole against Candida Species

Abstract

In light of the need for new antifungal regimens, we report that at noncandidacidal concentrations, the lactoferrin-derived peptide hLF(1-11), which is highly active against fluconazole-resistant Candida albicans, acts synergistically with fluconazole against this yeast and a fluconazole-sensitive C. albicans strain as well as C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. When these yeasts were exposed to hLF(1-11) for 5 min and then incubated with fluconazole, they were killed effectively, while no candidacidal activity was observed when they were incubated first with fluconazole and then exposed to the peptide, indicating that the candidacidal activity is initiated by the peptide while fluconazole is only required during the effector phase. Investigations of the effect of azide, which inhibits mitochondrial respiration, on the activity of combinations of hLF(1-11) and fluconazole against fluconazole-resistant C. albicans revealed that it inhibits this activity, even when added during the effector phase only. As expected, azide inhibited the accumulation of rhodamine 123 in mitochondria and the production and release of ATP by C. albicans that occurred upon exposure to the combination of hLF(1-11) and fluconazole. Accordingly, oxidized ATP (oATP), an antagonist of ATP receptors, completely blocked the candidacidal activity of the hLF(1-11)-fluconazole combination, whereas oATP did not block the activity when its presence was restricted to the effector phase. The candidacidal activity of combinations of hLF(1-11) and fluconazole, which is initiated by the peptide through the involvement of energized mitochondria, renders fluconazole-resistant C. albicans sensitive to this azole.

Antimicrobial Activity of Lactoferrin-Related Peptides and Applications in Human and Veterinary Medicine

“…The peptide was highly active against fluconazole-resistant Candida albicans at non-candidacidal concentrations, acted synergistically with fluconazole against this yeast and a fluconazole-sensitive C. albicans strain, as well as against C. glabrata, C. krusei, C. parapsilosis and C. tropicalis. When these yeasts were exposed to hLf(1-11) for five minutes and then incubated with fluconazole, they were effectively killed, while no candidacidal activity was observed when they were incubated first with fluconazole and then exposed to the peptide: this shows that the candidacidal activity is initiated by the peptide, whereas fluconazole is only required during the effector phase [53].…”

Comparable Efficacies of the Antimicrobial Peptide Human Lactoferrin 1-11 and Gentamicin in a Chronic Methicillin-Resistant Staphylococcus aureus Osteomyelitis Model

“…hLF1-11 has a broad antimicrobial spectrum in vitro against both bacteria and fungi (11,12,16). Furthermore, Nibbering et al demonstrated the efficacy of hLF1-11 in vivo, reducing the number of bacteria (MRSA) after systemic administration in the mouse thigh infection model (16).…”

CaIPF14030 negatively modulates intracellular ATP levels during the development of azole resistance in Candida albicans

“…It has also been documented that several peptides have synergistic activity against C albicans when combined with fluconazole due to inhibition of production and release of intracellular ATP [28][29][30] . Because CaIPF14030 plays a critical role in regulating intracellular ATP levels, the protein encoded by CaIPF14030 may be targeted by the inhibitors of intracellular ATP.…”