title: Metal-induced isomerization yields an intracellular chelator that disrupts bacterial iron homeostasis.
abstract: The dwindling supply of antibiotics that remain effective against drug-resistant bacterial pathogens has precipitated efforts to identify new compounds that inhibit bacterial growth using untapped mechanisms of action. Here, we report both (1) a high-throughput screening methodology designed to discover chemical perturbants of the essential, yet unexploited, process of bacterial iron homeostasis, and (2) our findings from a small-molecule screen of more than 30,000 diverse small molecules that led to the identification and characterization of two spiro-indoline-thiadiazoles that disrupt iron homeostasis in bacteria. We show that these compounds are intracellular chelators with the capacity to exist in two isomeric states. Notably, these spiroheterocyles undergo a transition to an open merocyanine chelating form with antibacterial activity that is specifically induced in the presence of its transition-metal target.
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Shannon B
authors.initials: SB
authors.lastname: Falconer
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Wang
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Sebastian S
authors.initials: SS
authors.lastname: Gehrke
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Cuneo
authors.affiliation: Department of Chemistry, McMaster University, Hamilton, ON L8S 4M1, Canada.
authors.forename: James F
authors.initials: JF
authors.lastname: Britten
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: ebrown@mcmaster.ca.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Brown
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006706:Homeostasis / Q000187:drug effects*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013141:Spiro Compounds / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D028561:Transition Elements / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001578:Benzopyrans; D007211:Indoles; D007502:Iron Chelating Agents; D009942:Organometallic Compounds; D054852:Small Molecule Libraries; D013141:Spiro Compounds; D013830:Thiadiazoles; D014157:Transcription Factors; D028561:Transition Elements; C114259:iron response regulator protein, Bacteria; C548873:merocyanine; C057812:indoline; D007501:Iron