Structural and Catalytic Architecture of the Cysteine Synthase Cys1a

Abstract

Antifungal drug resistance in Aspergillus fumigatus is a major global health concern. Due to the increasing frequency of drug-resistant strains, there is a growing need for novel antifungal drugs. Inhibition of the cysteine biosynthesis pathway in A. fumigatus represents a promising strategy for the development of antifungal adjuvants. Within this pathway, the previously uncharacterised enzyme AfuCys1a fulfils several desirable characteristics as an adjuvant target. To enable structure-based inhibitor design, AfuCys1a was structurally and functionally characterised using X-ray crystallography, biochemical assays, and comparative sequence and structural analysis. In the search for effective and viable adjuvants, this research characterises the catalytic mechanism and substrate recognition of AfuCys1a and identifies 2-picolinic acid and related compounds as promising starting points for inhibitor development, working towards the larger goal of combating rising deaths from infection by A. fumigatus.