title: Compounds that select against the tetracycline-resistance efflux pump.
abstract: We developed a competition-based screening strategy to identify compounds that invert the selective advantage of antibiotic resistance. Using our assay, we screened over 19,000 compounds for the ability to select against the TetA tetracycline-resistance efflux pump in Escherichia coli and identified two hits, β-thujaplicin and disulfiram. Treating a tetracycline-resistant population with β-thujaplicin selects for loss of the resistance gene, enabling an effective second-phase treatment with doxycycline.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Stone
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Baym
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tami D
authors.initials: TD
authors.lastname: Lieberman
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Institute of Science and Technology-Austria, Maria Gugging 3400, Klosterneuburg, Austria.
authors.forename: Remy
authors.initials: R
authors.lastname: Chait
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jon
authors.identifier: http://orcid.org/0000-0003-0213-8356
authors.initials: J
authors.lastname: Clardy
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Biology and Department of Computer Science, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Roy
authors.initials: R
authors.lastname: Kishony
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004221:Disulfiram / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013753:Tetracycline Resistance / Q000187:drug effects*; D014334:Tropolone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D039821:Monoterpenes; D014334:Tropolone; D004221:Disulfiram; C009479:beta-thujaplicin