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Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy

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

PLoS Biol. 2016 Sep 15;14(9):e1002552.

PMID: 27631336

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP59702317	Piperacillin Related Compound E		59702-31-7	Price

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