Acetohydroxyacid Synthase (AHAS) as a Promising and Underexplored Target for the Development of New Antifungal Agents

Fungi are ubiquitous and play crucial ecological roles, but fungal infections pose serious threats to human, animal, and environmental health, with a significant economic and social burden. Current antifungal therapies face challenges, such as limited drugs, toxicity, and resistance, highlighting the urgent need for drugs with new mechanisms of action. The enzyme acetohydroxyacid synthase (AHAS) is a promising target, as it is involved in branched-chain amino acid biosynthesis, a pathway lacking in animals and already explored in herbicide development.

We conducted an integrative review covering the antifungal potential of known AHAS inhibitors and the development of novel inhibitors with antifungal activity within the PubMed, ScienceDirect, and Web of Science databases.

A total of 590 articles were obtained, and after applying the inclusion and exclusion criteria, 17 articles were selected. The review identified commercial herbicides as potent AHAS inhibitors of plant and animal pathogenic fungi and to have a broad spectrum of antifungal activity against many species, such as Candida albicans, C. auris, Cryptococcus neoformans, Aspergillus fumigatus, and Saccharomyces cerevisiae.

Based on these results, several compounds were designed, synthesized, and evaluated as antifungal agents, showing promising inhibitory properties against fungal AHAS and growth. Structural features of AHAS from different organisms were also investigated to guide drug development.

Considering structural insights and experimental data, AHAS inhibitors showed promising profile as broad-spectrum antifungals, with low toxicity to humans and the environment, supporting a One Health approach to control fungal infections across human, animal, and environmental health.