Format

Send to

Choose Destination
Cell Chem Biol. 2016 Nov 17;23(11):1351-1361. doi: 10.1016/j.chembiol.2016.09.012. Epub 2016 Oct 20.

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

Author information

1
Department of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Graduate Program in Microbiology & Immunology, Vanderbilt University, Nashville, TN 37232, USA.
2
Department of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
3
Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ 08901, USA.
4
Department of Chemistry, Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
5
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
6
Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ 08901, USA. Electronic address: jmboyd@aesop.rutgers.edu.
7
Department of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Veterans Affairs Tennessee Valley Healthcare Services, Nashville, TN 37232, USA. Electronic address: eric.skaar@vanderbilt.edu.

Abstract

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.

KEYWORDS:

SaeRS; Staphylococcus; aconitase; fermentation; iron-sulfur cluster; virulence factors

PMID:
27773628
PMCID:
PMC5117899
DOI:
10.1016/j.chembiol.2016.09.012
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center