A Small-Molecule Inhibitor of Iron-Sulfur Cluster Assembly Uncovers a Link between Virulence Regulation and Metabolism in Staphylococcus aureus.

Choby JE, Mike LA, Mashruwala AA, Dutter BF, Dunman PM, Sulikowski GA, Boyd JM, Skaar EP
Cell Chem Biol. 2016 23 (11): 1351-1361

PMID: 27773628 · PMCID: PMC5117899 · DOI:10.1016/j.chembiol.2016.09.012

The rising problem of antimicrobial resistance in Staphylococcus aureus necessitates the discovery of novel therapeutic targets for small-molecule intervention. A major obstacle of drug discovery is identifying the target of molecules selected from high-throughput phenotypic assays. Here, we show that the toxicity of a small molecule termed '882 is dependent on the constitutive activity of the S. aureus virulence regulator SaeRS, uncovering a link between virulence factor production and energy generation. A series of genetic, physiological, and biochemical analyses reveal that '882 inhibits iron-sulfur (Fe-S) cluster assembly most likely through inhibition of the Suf complex, which synthesizes Fe-S clusters. In support of this, '882 supplementation results in decreased activity of the Fe-S cluster-dependent enzyme aconitase. Further information regarding the effects of '882 has deepened our understanding of virulence regulation and demonstrates the potential for small-molecule modulation of Fe-S cluster assembly in S. aureus and other pathogens.

Copyright © 2016 Elsevier Ltd. All rights reserved.

MeSH Terms (14)

Aconitate Hydratase Anti-Bacterial Agents Bacterial Proteins Drug Discovery Humans Iron-Sulfur Proteins Protein Kinases Signal Transduction Small Molecule Libraries Staphylococcal Infections Staphylococcus aureus Transcription Factors Virulence Virulence Factors

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