Development of novel fungal Arp2/3 complex inhibitors

Pathogenic fungi are a potential threat for infection and death in immunocompromised individuals, recipients of chemotherapy, and other hospital patients. The WHO has identified Candida albicans, Candida auris, Aspergillus fumigatus, and Cryptococcus neoformans as being of critical importance among fungal pathogens. Since many fungal pathogens are drug-resistant or form protective biofilms, it is important to consider novel therapeutic targets that play a role in fungal pathogenesis, such as the Arp2/3 complex. The Arp2/3 complex is the branched actin nucleation factor that promotes actin polymerization, which in turn plays a critical role in these pathogens' normal biology and the formation of biofilms. This project aims to identify compounds that specifically inhibit fungal Arp2/3 complexes. The fungal Arp3 subunit contains 2 amino acid substitutions within the binding pocket for a previously identified mammalian Arp2/3 complex inhibitor. In silico screening was conducted using the structure of Arp3, with several compounds being identified as potential binding partners to fungal Arp3. Here, I describe my use of reconstituted actin polymerization assays to identify a novel lead compound with inhibition activity and specificity to fungal Arp2/3 complexes.