Invasive fungal infections affect over two million people per year world-wide and kill more people each year than malaria, or TB, or breast cancer, or prostate cancer. There are only four classes of antifungal drugs available to treat these infections, and their use is complicated by off-target toxicity, unfavourable drug-drug interactions and increasing rates of antifungal resistance. Recognising the magnitude and complexity of the threat posed by fungal pathogens, and the urgent need for novel antifungal agents, in October 2022, the WHO released the first ever Fungal Priority Pathogens List to Guide Research, Development and Public Health Action1. Recommendations included focussing R&D on innovative antifungal agents with no cross resistance to existing antifungal classes and with new modes-of-action, and optimising combination therapies to prevent further antifungal resistance, enhance efficacy and minimise toxicity.
Utilising recent innovations in chemistry, we developed synthetic bioactive polymers that mimic common properties of antifungal peptides. Libraries of positively charged polymers were screened to identify lead candidates active against fungal priority pathogens with good biocompatibility2. Our lead polymers retained activity against Candida albicans isolates resistant to existing antifungals (amphotericin B, fluconazole and caspofungin). To determine the mode(s)-of-action, the transcriptome of C. albicans cells grown in the presence of our lead polymers was analysed and indicated that our most active polymer affected protein glycosylation and cell membranes. Microscopy experiments confirmed disruption to N-mannans attached cell wall proteins on the C. albicans cell surface, and cell death by membrane lysis. Checkerboard assays revealed in vitro synergy between our lead polymer and caspofungin or fluconazole. Synergistic combinations prevented infection of human epithelial cells in vitro, improved fungal clearance by macrophages, and show promise in vivo. Importantly, we were unable to lab-evolve resistance to our synergistic combinations.
Our novel synthetic bioactive polymers therefore have a mode of action distinct from existing antifungals and have the potential to be utilised as combination therapies to enhance efficacy, minimise toxicity and mitigate antifungal resistance before it merges in the clinic. This work aligns with the WHO’s recommendations for the development of novel antifungal agents to combat the growing threat of invasive fungal infections.