Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy

Dilay Hazal Ayhan, Yusuf Talha Tamer, Mohammed Akbar, Stacey M. Bailey, Michael Wong, Seth M. Daly, David E. Greenberg, Erdal Toprak

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1002552
JournalPLoS Biology
Volume14
Issue number9
DOIs
StatePublished - Sep 15 2016

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Bacterial Genes
Genes
antibiotics
Anti-Bacterial Agents
Oligomers
genes
Escherichia coli
Bacteria
bacteria
Microbial Drug Resistance
hypersensitivity
antibiotic resistance
Public health
Medical problems
public health
Hypersensitivity
Toxicity
Public Health
toxicity
Cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Ayhan, D. H., Tamer, Y. T., Akbar, M., Bailey, S. M., Wong, M., Daly, S. M., ... Toprak, E. (2016). Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy. PLoS Biology, 14(9), [e1002552]. https://doi.org/10.1371/journal.pbio.1002552

Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy. / Ayhan, Dilay Hazal; Tamer, Yusuf Talha; Akbar, Mohammed; Bailey, Stacey M.; Wong, Michael; Daly, Seth M.; Greenberg, David E.; Toprak, Erdal.

In: PLoS Biology, Vol. 14, No. 9, e1002552, 15.09.2016.

Research output: Contribution to journalArticle

Ayhan DH, Tamer YT, Akbar M, Bailey SM, Wong M, Daly SM et al. Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy. PLoS Biology. 2016 Sep 15;14(9). e1002552. https://doi.org/10.1371/journal.pbio.1002552
Ayhan, Dilay Hazal ; Tamer, Yusuf Talha ; Akbar, Mohammed ; Bailey, Stacey M. ; Wong, Michael ; Daly, Seth M. ; Greenberg, David E. ; Toprak, Erdal. / Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy. In: PLoS Biology. 2016 ; Vol. 14, No. 9.
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