SA-XV, a 15-amino acid fragment of host defense peptide S100A12, targets mitochondria and is protective against fungal infections

Fungal infections are a huge emerging crisis, with more than 2 million people infected worldwide annually. Corneal infections caused by fungus are the major cause of vision loss and often warrant corneal transplantation. Both Fusarium spp. and Candida spp. are critical etiological agents of fungal keratitis and also common causes for invasive fungal infections with high mortality rates. In the previous work, we described growth inhibition of Fusarium spp. by S100A12, a host antimicrobial peptide. Here, to optimize a potential therapeutic, we have studied a 15-amino acid fragment of S100A12, SA-XV. Interestingly, SA-XV demonstrated remarkable antifungal activities, similar to the parent peptide, against both Fusarium spp. and Candida spp. SA-XV is a cell-penetrating peptide, and once internalized, it binds to fungal DNA, halts the cell cycle, and disrupts mitochondria, leading to the generation of reactive oxygen species and cell damage. The atomistic structure of the peptide determined by NMR reveals that SA-XV associates with the fungal membrane. The structural changes in SA-XV from α-helical to random coil conformation were observed in all-atom simulations. In addition, SA-XV aids in wound healing of corneal epithelial cells and attenuates the fungal burden in a murine model of fungal keratitis. Our results clearly demonstrate SA-XV as a promising antifungal candidate that targets both filamentous and nonfilamentous fungi for alternative therapeutic interventions.