The GPCR antagonist PPTN synergizes with caspofunginproviding increased fungicidal activity against Aspergillus fumigatus

Fungal pathogens pose a serious threat to human health with Candida and Aspergillus spp. representing some of the most significant opportunistic invaders. Aspergillus fumigatus causes aspergillosis, one of the most prevalent fungal diseases of humans. There is a limited number of drugs available to combat these infections, and antifungal drug resistance is on the rise. In this manuscript, we show 4 – [4 – (4 – Piperidinyl) phenyl] – 7 – [4- (-(trifluoromethyl) phenyl] – 2 -naphthalenecarboxylic acid (PPTN), a highly specific antagonist of the human P2Y14 receptor, is a promising antifungal adjuvant against diverse fungal pathogens. PPTN interacts with caspofungin (CAS), ibrexafungerp, voriconazole (VOR), and amphotericin against A. fumigatus CAS- and VOR-resistant clinical isolates, and also CAS against Candida spp and Cryptococcus neoformans. The combination of PPTN and CAS increase cell death in A. fumigatus. In the model yeast Saccharomyces cerevisiae, heterozygous deletion of genes involved in chromatin remodeling results in PPTN hypersensitivity and in A. fumigatus PPTN can have increased fungicidal activity when combined with the histone deacetylase inhibitor trichostatin A and the DNA methyltransferase inhibitor 5-azacytidine. Finally, PPTN has reduced toxicity to human immortalized cell lineages and partially clears A. fumigatus conidia infection in A549 pulmonary epithelial cells. Our results indicate that PPTN is a novel adjuvant antifungal drug against fungal diseases caused by A. fumigatus and Candida spp.