Overcoming antifungal resistance in azole resistant Candida auris through molecular harpoon-based drug design

Abstract

Antifungal research represents a gap in the infectious disease sector with less than 1.5% of funding into infectious diseases spent on antifungal research and development. To address the gap, this project investigated the potential of a class of amphiphiles, comprised of an aromatic head group and polyether tail and with previously presented antimicrobial ability, to act as novel antifungal agents.
For this research small amphiphilic molecules with a phenol derivative head group and polyether tail, termed molecular harpoons, were synthesised. Over 30 compounds were prepared, mainly by a simple two step method, and their antimicrobial effects assessed by disk diffusion and minimum inhibitory concentration assays. Other studies included the determination of six yeast lipidomes and in silico protein docking studies to attempt to identify the harpoons’ mode of action.
Key findings from this research show that the unsaturated harpoons generally have a low MIC in the range of 0.163 to 1.563 mg mL-1 and some show specificity for multidrug-resistant Candida auris. Correlations between lipidomes and antifungal activity were inconclusive but in silico experiments suggest that the harpoons do not inhibit the same enzymatic pathways targeted by some existing classes of antifungal agents. Critical micelle concentrations were far higher than the concentration required for antifungal effects demonstrating that the harpoons do not function as simple surfactants.

Date of Award	May 2026
Original language	English
Awarding Institution	University of Brighton
Supervisor	Peter Cragg (Supervisor), Joao Inacio Silva (Supervisor), Marcus Dymond (Supervisor) & Graham Pattison (Supervisor)