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.
Highlights
Antibiotic resistance is an important public health problem that emerged shortly after the discovery of antibiotics [1,2]
While genome sequencing and genetic manipulation tools have elucidated many resistance mechanisms, these tools have not yet been developed into successful therapeutics. One tool with such potential are peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), which are synthetic DNA/
Therapeutics, holds several patents related to PPMOs, and receives license-related royalties for these
Summary
Antibiotic resistance is an important public health problem that emerged shortly after the discovery of antibiotics [1,2]. Pathogenic bacteria are either intrinsically resistant to some antibiotics or they acquire resistance via spontaneous mutations or horizontal gene transfer. These resistance mechanisms include deactivation or modification of antibiotics, pumping out antibiotics via efflux pumps, protection of antibiotic targets, and mutations in the target enzymes that decrease antibiotic affinity [3]. By using novel gene-editing tools such as CRISPR-CAS9 or engineered bacteriophages, it is possible to edit bacterial genomes to modulate antibiotic sensitivity of bacteria and design sequencespecific antimicrobials [8,9,10]. Gene-editing tools are currently difficult to implement given the practical and ethical problems with mutating bacterial genomes within an infected human patient. We designed antisense oligomers, which target the mRNA of bacterial resistance genes, preventing translation in a sequence-specific manner [11]
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