Ayhan, Dilay HazalTamer, Yusuf TalhaAkbar, MohammedBailey, Stacey M.Wong, MichaelDaly, Seth M.Greenberg, David E.Toprak, Erdal2016-11-182016Ayhan, Dilay Hazal, Yusuf Talha Tamer, Mohammed Akbar, Stacey M. Bailey, Michael Wong, Seth M. Daly, David E. Greenberg, and Erdal Toprak. 2016. “Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy.” PLoS Biology 14 (9): e1002552. doi:10.1371/journal.pbio.1002552. http://dx.doi.org/10.1371/journal.pbio.1002552.1544-9173http://nrs.harvard.edu/urn-3:HUL.InstRepos:29407562The 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.en-USMedicine and Health SciencesPharmacologyDrugsAntimicrobialsAntibioticsBiology and Life SciencesMicrobiologyMicrobial ControlAntimicrobial ResistanceAntibiotic ResistancePhysical SciencesMaterials ScienceMaterials by StructureOligomersGeneticsMutationDeletion MutationMedical MicrobiologyMicrobial PathogensBacterial PathogensPathology and Laboratory MedicinePathogensDrug InteractionsMaterials by AttributePigmentsDyesFluorescent DyesBiology and life sciencesBiochemistryNucleic acidsRNAMessenger RNAJournal Article2016-11-1810.1371/journal.pbio.1002552