title: Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy.
abstract: The lack of effective and well-tolerated therapies against antibiotic-resistant bacteria is a global public health problem leading to prolonged treatment and increased mortality. To improve the efficacy of existing antibiotic compounds, we introduce a new method for strategically inducing antibiotic hypersensitivity in pathogenic bacteria. Following the systematic verification that the AcrAB-TolC efflux system is one of the major determinants of the intrinsic antibiotic resistance levels in Escherichia coli, we have developed a short antisense oligomer designed to inhibit the expression of acrA and increase antibiotic susceptibility in E. coli. By employing this strategy, we can inhibit E. coli growth using 2- to 40-fold lower antibiotic doses, depending on the antibiotic compound utilized. The sensitizing effect of the antisense oligomer is highly specific to the targeted gene's sequence, which is conserved in several bacterial genera, and the oligomer does not have any detectable toxicity against human cells. Finally, we demonstrate that antisense oligomers improve the efficacy of antibiotic combinations, allowing the combined use of even antagonistic antibiotic pairs that are typically not favored due to their reduced activities.
authors.affiliation: Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America.
authors.forename: Dilay Hazal
authors.identifier: 0000-0002-0497-3294
authors.initials: DH
authors.lastname: Ayhan
authors.affiliation: Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Molecular Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Yusuf Talha
authors.identifier: 0000-0002-5901-842X
authors.initials: YT
authors.lastname: Tamer
authors.affiliation: Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Mohammed
authors.identifier: 0000-0003-1832-2043
authors.initials: M
authors.lastname: Akbar
authors.affiliation: Sarepta Therapeutics, Cambridge, Massachusetts, United States of America.
authors.forename: Stacey M
authors.identifier: 0000-0002-8356-8384
authors.initials: SM
authors.lastname: Bailey
authors.affiliation: Sarepta Therapeutics, Cambridge, Massachusetts, United States of America.|Harvard Medical School, Cambridge, Massachusetts, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Daly
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Greenberg
authors.affiliation: Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Erdal
authors.initials: E
authors.lastname: Toprak
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D005798:Genes, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010878:Piperacillin / Q000494:pharmacology; D013420:Sulfamethoxazole / Q000494:pharmacology; D000078142:Tazobactam; D014295:Trimethoprim / Q000494:pharmacology
chemical_list: C000596829:AcrAB-TolC protein, E coli; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D010397:Penicillanic Acid; D014295:Trimethoprim; D013420:Sulfamethoxazole; D000078142:Tazobactam; D010878:Piperacillin