Data from: Identification and evaluation of novel acetolactate synthase inhibitors as antifungal agents

High-throughput phenotypic screening against yeast Saccharomyces cerevisiae revealed a series of triazolo-pyrimidine-sulfonamide compounds with broad-spectrum antifungal activity, no significant cytotoxicity, and low protein binding. To elucidate the target of this series we have applied a chemogenomic profiling approach using the S. cerevisiae deletion collection. All compounds of the series yielded highly similar profiles that suggested acetolactate synthase (Ilv2p, catalyzes the first common step in branched chain amino acid biosynthesis) as a possible target. High correlation to profiles of known Ilv2p inhibitors like chlorimuron-ethyl provided further evidence for a similar mechanism of action. Genome-wide mutagenesis in S. cerevisiae identified 13 resistant clones with 3 different mutations in the catalytic subunit of acetolactate synthase that also conferred cross-resistance to established Ilv2p inhibitors. Mapping the mutations into the published Ilv2p crystal structure outlined the chlorimuron-ethyl binding cavity and it was possible to dock the triazolo-pyrimidine-sulfonamide compound into this pocket in silico. However, fungal growth inhibition could be bypassed through supplementation with exogenous branched chain amino acids, or by the addition of serum to the medium in all of the fungal organisms tested except for Aspergillus fumigatus. Thus, these data support the identification of triazolo-pyrimidine-sulfonamide as inhibitors of acetolactate synthase but suggest that targeting may be compromised due to the possibility of nutrient bypass in vivo.