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Identification and Evaluation of Novel Acetolactate Synthase Inhibitors as Antifungal Agents

Richie, Daryl and Thompson, Katherine and Studer, Christian and Aust, Thomas and Riedl, Ralph and Estoppey, David and Zabawa, Thomas and Drumm Iii, Joseph and Cotesta, Simona and Eichenberger, Juerg and Schuierer, Sven and Hartmann, Nicole and Movva, Rao and Tallarico, John and Ryder, Neil and Hoepfner, Dominic (2013) Identification and Evaluation of Novel Acetolactate Synthase Inhibitors as Antifungal Agents. Antimicrobial Agents and Chemotherapy, 57 (5). pp. 2272-2280. ISSN 0066-4804

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.

Item Type: Article
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Keywords: Acetolactate synthase, Ilv2, Ilv6, HIP HOP, antifungal agents, branched chain amino acid synthesis, target identification, sulfonamide, triazolo-pyrimidine-sulfonamide
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8219

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