How does a new antimicrobial kill the fungi that invade immunosuppressed patients?

Olorofim, the first member of the new Orotomide class of antifungals [1], is fungicidal against the most common human mould pathogen Aspergillus fumigatus (Af) [2], and is highly effective in immunosuppressed invasive fungal models [3]. Cidality is important, as fungistatic therapies often carry high mortality (50-80%). There are currently only 3 distinct antifungal classes for serious systemic infections. Azoles, the dominant drug class, still have significant mortality, and resistance is particularly high in Northern Europe. Amphotericin is highly toxic. Echinocandins are only fungistatic to Af. New agents with novel mechanisms of action are urgently required.
Olorofim inhibits dihydroorotic acid dehydrogenase (DHODH), an essential ubiquitous enzyme in pyrimidine synthesis, strongly selecting for Af isozyme cf human (2000:1). In model budding yeast, pyrimidine starvation is lethal more rapidly (t.5 16 hours) than starvation for any metabolite tested (e.g. phosphate t.5 25 days) because there is no pyrimidine starvation programme [4].
Greater fundamental understanding of Olorofim will support development both of further orotomides targeting the same enzyme in other pathogens and of new antimicrobials with related targets.
The mode of cell death is still not clear. Pyrimidines are building blocks not only for nucleic acids, but also for phospholipids and fungal cell wall glucans. The latter is the most obvious target for cidality by Olorofim, as it causes Af hyphal lysis [2]. The lack of cidality by echinocandins, which also target the cell wall, suggests that additional, non-cell wall pathways targeted by Olorofim underlie its success.