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Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy

Fig 5

Targeting resistance genes with acrA-PPMO increases efficacy of antibiotic combinations and even makes the use of antagonistic antibiotic pairs possible.

(A) Conceptual representation of the possible effects of efflux inhibition on the use of antibiotics pairs. Blue and black lines represent the MIC lines in two-dimensional gradients of drug pairs for bacteria with and without acrA-PPMO, respectively. The left panel represents an increase in susceptibility to antibiotic B, the middle panel represents an increase to antibiotic A, and the right panel represents an increase to both antibiotics. (B) MIC lines determined in two-dimensional gradients of (left) trimethoprim-sulfamethoxazole and (right) trimethoprim-piperacillin/tazobactam for wild type E. coli (black line), with 10 μM acrA-PPMO (blue line), or the acrA deletion mutant (cyan line). (C) Bar graphs demonstrating the efficacy of antibiotic combinations shown in (B). Area under the MIC curves in (B) are significantly reduced relative to the wild type E. coli (bars with black diagonal lines) for both antibiotic combinations when 10 μM acrA-PPMO (blue bars) is used or acrA (cyan bars) is physically deleted. All measurements were done in triplicate, and p-values for significance were calculated with Student’s t-test.

Fig 5