The GPCR antagonist PPTN synergizes with caspofunginproviding increased fungicidal activity against <i>Aspergillus fumigatus</i>

<br>Fungal pathogens pose a serious threat to human health with <i>Candida </i>and <i>Aspergillus</i><i> </i>spp. representing some of the most significant opportunistic invaders. <i>Aspergillus</i><i> </i><i>fumigatus</i><i> </i>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 <i>A. </i><i>fumigatus</i><i> </i>CAS- and VOR-resistant clinical isolates, and also CAS against <i>Candida </i>spp and <i>Cryptococcus</i><i> </i><i>neoformans</i>. The combination of PPTN and CAS increase cell death in <i>A. </i><i>fumigatus</i>. In the model yeast <i>Saccharomyces cerevisiae,</i> heterozygous deletion of genes involved in chromatin remodeling results in PPTN hypersensitivity and in <i>A. </i><i>fumigatus</i> 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 <i>A. fumigatus</i> conidia infection in A549 pulmonary epithelial cells. Our results indicate that PPTN is a novel adjuvant antifungal drug against fungal diseases caused by <i>A. </i><i>fumigatus</i> and <i>Candida </i>spp.