title: A differential drug screen for compounds that select against antibiotic resistance.
abstract: Antibiotics increase the frequency of resistant bacteria by providing them a competitive advantage over sensitive strains. Here, we develop a versatile assay for differential chemical inhibition of competing microbial strains, and use it to identify compounds that preferentially inhibit tetracycline-resistant relative to sensitive bacteria, thus "inverting" selection for resistance. Our assay distinguishes compounds selecting directly against specific resistance mechanisms and compounds whose selection against resistance is based on their physiological interaction with tetracycline and is more general with respect to resistance mechanism. A pilot screen indicates that both types of selection-inverting compounds are secreted by soil microbes, suggesting that nature has evolved a repertoire of chemicals that counteracts antibiotic resistance. Finally, we show that our assay can more generally permit simple, direct screening for drugs based on their differential activity against different strains or targets.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Remy
authors.initials: R
authors.lastname: Chait
authors.forename: Shreya
authors.initials: S
authors.lastname: Shrestha
authors.forename: Aakash Kaushik
authors.initials: AK
authors.lastname: Shah
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.forename: Roy
authors.initials: R
authors.lastname: Kishony
mesh_terms: D000362:Agar / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008826:Microbial Sensitivity Tests; D020033:Protein Isoforms; D012987:Soil; D013752:Tetracycline / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D020033:Protein Isoforms; D012987:Soil; D000362:Agar; D013752:Tetracycline