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PLoS Biol. 2016 Sep 15;14(9):e1002552. doi: 10.1371/journal.pbio.1002552. eCollection 2016 Sep.

Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy.

Author information

1
Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
2
Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America.
3
Department of Molecular Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
4
Sarepta Therapeutics, Cambridge, Massachusetts, United States of America.
5
Harvard Medical School, Cambridge, Massachusetts, United States of America.
6
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
7
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
8
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

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.

PMID:
27631336
PMCID:
PMC5025249
DOI:
10.1371/journal.pbio.1002552
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

MW and SMB are employees of Sarepta Therapeutics that hold numerous patents on the methods of synthesis and use of PPMOs. DEG receives research support from Sarepta Therapeutics, holds several patents related to PPMOs, and receives license-related royalties for these. All other authors declare no competing financial interest.

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