title: A Small-Molecule Inhibitor of Iron-Sulfur Cluster Assembly Uncovers a Link between Virulence Regulation and Metabolism in Staphylococcus aureus.
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.
authors: Department of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Graduate Program in Microbiology & Immunology, Vanderbilt University, Nashville, TN 37232, USA.
authors: Jacob E
authors: JE
authors: Choby
authors: Department of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Laura A
authors: LA
authors: Mike
authors: Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ 08901, USA.
authors: Ameya A
authors: AA
authors: Mashruwala
authors: Department of Chemistry, Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors: Brendan F
authors: BF
authors: Dutter
authors: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors: Paul M
authors: PM
authors: Dunman
authors: Department of Chemistry, Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors: Gary A
authors: GA
authors: Sulikowski
authors: Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ 08901, USA. Electronic address: jmboyd@aesop.rutgers.edu.
authors: Jeffrey M
authors: JM
authors: Boyd
authors: 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.
authors: Eric P
authors: EP
authors: Skaar
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014774:Virulence / Q000187:drug effects; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D007506:Iron-Sulfur Proteins; C433805:SaeR protein, Staphylococcus aureus; D054852:Small Molecule Libraries; D014157:Transcription Factors; D037521:Virulence Factors; D011494:Protein Kinases; C527351:SaeS protein, Staphylococcus aureus; D000154:Aconitate Hydratase
keywords: SaeRS; Staphylococcus; aconitase; fermentation; iron-sulfur cluster; virulence factors