Screen identifies four compounds with novel antifungal activity against Candida albicans
A high-throughput screen of 20,000 compounds identified four compounds with novel antifungal activity against Candida albicans. Z56842335 cleared infection in a Galleria mellonella model and showed a metal-dependent mode of action.
A high-throughput screen of 20,000 compounds against the opportunistic fungal pathogen Candida albicans identified four promising compounds with novel antifungal activity: Z1199266541, Z1024453766, Z56842335, and Z126932704. Among the candidates, Z56842335 emerged as a lead compound, effectively clearing infection caused by Candida albicans in a Galleria mellonella infection model.
The compounds were characterized in vitro to assess their spectrum of activity, efficacy against a fluconazole-resistant isolate (CaCi-17), and effectiveness in combination treatments, followed by in vivo evaluation in a Galleria mellonella infection model. Mechanistic analyses revealed that the antifungal activity of Z56842335 is mitigated by supplementation with iron, copper, and zinc, indicating a metal-dependent mode of action.
Despite its apparent metal-binding capacity, Z56842335 displays a narrow spectrum of activity, targeting only C. albicans and, to a lesser extent C. dubliniensis. This selectivity suggests that, in addition to metal availability, species-specific factors such as differences in metal acquisition, intracellular metal buffering, or compound uptake or accumulation may contribute to susceptibility.
Fungal infections represent a growing global health concern, aggravated by the paucity of effective antifungal therapies and the rapid rise of drug resistance. The development of new treatments is challenging due to the shared eukaryotic biology of fungi and human hosts, which restricts selective molecular targets and contributes to issues such as host toxicity and fungistatic activity.