Global burden of invasive fungal infections (IFIs) account for more than 1.6 million deaths annually. Treatment of these deadly infections is currently limited to four classes, three of which target the fungal membrane. Human and fungal cells share a high degree of genomic similarity therefore antifungals are often limited by drug-associated toxicity due to off-target effects on human cells. Emergence and increasing prevalence of multidrug-resistant (MDR) fungal strains further restricts the utility of current antimycotics. For example, Candida auris is a global health threat with >90% of clinical isolates resistant to at least one class of antifungals and pan-resistant strains have been reported. There is an urgent need to develop new antifungals.

Cationic cyclic peptides (CCPs) have been revealed to have broad-spectrum antimicrobial properties, owing to their cationic charges that can interact with the negatively charged phospholipids within fungal cell membrane. AR268, is an exciting novel CCP recently developed within the Robertson group. AR268 demonstrated potent fungicidal activity, comparable to current antifungals, towards the pathogenic yeasts C. auris (azole-resistant and susceptible), Candida albicans and Cryptococcus neoformans. This presentation will report on AR268 and the associated structure-activity relationship studies.