title: A Hybrid Drug Limits Resistance by Evading the Action of the Multiple Antibiotic Resistance Pathway.
abstract: Hybrid drugs are a promising strategy to address the growing problem of drug resistance, but the mechanism by which they modulate the evolution of resistance is poorly understood. Integrating high-throughput resistance measurements and genomic sequencing, we compared Escherichia coli populations evolved in a hybrid antibiotic that links ciprofloxacin and neomycin B with populations evolved in combinations of the component drugs. We find that populations evolved in the hybrid gain less resistance than those evolved in an equimolar mixture of the hybrid's components, in part because the hybrid evades resistance mediated by the multiple antibiotic resistance (mar) operon. Furthermore, we find that the ciprofloxacin moiety of the hybrid inhibits bacterial growth whereas the neomycin B moiety diminishes the effectiveness of mar activation. More generally, comparing the phenotypic and genotypic paths to resistance across different drug treatments can pinpoint unique properties of new compounds that limit the emergence of resistance.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA.
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Wang
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Stone
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA.
authors.forename: Tami D
authors.initials: TD
authors.lastname: Lieberman
authors.affiliation: Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Shavit
authors.affiliation: Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa, Israel chtimor@tx.technion.ac.il rkishony@technion.ac.il.
authors.forename: Timor
authors.initials: T
authors.lastname: Baasov
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA Faculties of Biology and Computer Science, Technion-Israel Institute of Technology, Technion City, Haifa, Israel chtimor@tx.technion.ac.il rkishony@technion.ac.il.
authors.forename: Roy
authors.initials: R
authors.lastname: Kishony
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D005075:Biological Evolution; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype
chemical_list: D000900:Anti-Bacterial Agents
keywords: antibiotic resistance; experimental evolution; hybrid drug; multidrug resistance