Richie DL~Hoepfner D, 2013

Pubmed ID 23478965
Title Identification and evaluation of novel acetolactate synthase inhibitors as antifungal agents.
Authors Daryl L Richie, Katherine V Thompson, Christian Studer, Vivian C Prindle, Thomas Aust, Ralph Riedl, David Estoppey, Jianshi Tao, Jessica A Sexton, Thomas Zabawa, Joseph Drumm, Simona Cotesta, Jürg Eichenberger, Sven Schuierer, Nicole Hartmann, N Rao Movva, John A Tallarico, Neil S Ryder, Dominic Hoepfner
Abstract High-throughput phenotypic screening against the yeast Saccharomyces cerevisiae revealed a series of triazolopyrimidine-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, which catalyzes the first common step in branched-chain amino acid biosynthesis) as a possible target. The high correlation with 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 of the mutations into the published Ilv2p crystal structure outlined the chlorimuron-ethyl binding cavity, and it was possible to dock the triazolopyrimidine-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 the triazolopyrimidine-sulfonamide compounds as inhibitors of acetolactate synthase but suggest that targeting may be compromised due to the possibility of nutrient bypass in vivo.
Citation Antimicrob. Agents Chemother. 2013; 57:2272-80

Datasets

Download the list of datasets
Paper Phenotype Condition Reference Collection Tested mutants Data Details
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 1 [3 uM] hom 4,417 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 1 [4 uM] hom 4,348 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 2 [6 uM] hom 4,474 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 3 [1.5 uM] hom 4,490 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 4 [10 uM] hom 4,490 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 5 [8 uM] hom 4,466 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 6 [0.5 uM] hom 4,490 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 7 [4 uM] hom 4,500 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 8 [4 uM] hom 4,500 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) sulfometuron methyl [30 uM] hom 4,445 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) Chlorimuron ethyl [10 uM] hom 4,445 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 1 [3 uM] het 5,718 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 1 [4 uM] het 5,717 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 2 [6 uM] het 5,760 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 3 [1.5 uM] het 5,753 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 4 [10 uM] het 5,753 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 5 [8 uM] het 5,749 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 6 [0.5 uM] het 5,753 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 7 [4 uM] het 5,753 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) compound 8 [4 uM] het 5,753 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) sulfometuron methyl [30 uM] het 5,731 Quantitative
Richie DL~Hoepfner D, 2013 growth (relative abundance in pooled culture) Chlorimuron ethyl [10 uM] het 5,731 Quantitative

Curation history

Data

Jan. 15, 2018 Ready to load.
Jan. 31, 2018 Loaded.

Tested strains

Jan. 15, 2018 Ready to load.
Jan. 31, 2018 Loaded.