title: Decoupling Activation of Heme Biosynthesis from Anaerobic Toxicity in a Molecule Active in Staphylococcus aureus.
abstract: Small molecules active in the pathogenic bacterium Staphylococcus aureus are valuable tools for the study of its basic biology and pathogenesis, and many molecules may provide leads for novel therapeutics. We have previously reported a small molecule, 1, which activates endogenous heme biosynthesis in S. aureus, leading to an accumulation of intracellular heme. In addition to this novel activity, 1 also exhibits toxicity towards S. aureus growing under fermentative conditions. To determine if these activities are linked and establish what features of the molecule are required for activity, we synthesized a library of analogs around the structure of 1 and screened them for activation of heme biosynthesis and anaerobic toxicity to investigate structure-activity relationships. The results of this analysis suggest that these activities are not linked. Furthermore, we have identified the structural features that promote each activity and have established two classes of molecules: activators of heme biosynthesis and inhibitors of anaerobic growth. These molecules will serve as useful probes for their respective activities without concern for the off target effects of the parent compound.
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Dutter
authors.forename: Laura A
authors.initials: LA
authors.lastname: Mike
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reid
authors.affiliation: Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Chong
authors.affiliation: Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramos-Hunter
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
authors.affiliation: Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Sulikowski
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001421:Bacteria, Anaerobic / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; 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; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011720:Pyrazoles; D054852:Small Molecule Libraries; D006418:Heme; D007501:Iron; D010100:Oxygen