Alkylation-based optimization of antifungal FPPS inhibitors yields a potent, broad-spectrum lipophilic zoledronate derivative

At least 1.6 million lives are lost every year to invasive fungal infections, and topical infections like candidiasis and dermatophytosis are extremely widespread. The current arsenal of antifungal drugs is severely limited; most are either toxic to humans or have a narrow spectrum of activity, and antifungal resistance is an emerging concern. These problems demand new druggable targets with approaches that can mitigate resistance. Here, we build on a body of work that found the disruption of squalene synthesis by bisphosphonates to be a promising approach for synergistically enhancing azole antifungals and preventing the development of resistance. We find an alkylated derivative of the bisphosphonate zoledronate, termed 10-ZOL, to be highly antifungal <i>in vitro</i> and <i>in vivo</i> against an extremely diverse spectrum of fungal pathogens, with minimal toxicity to mammalian cells.