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Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy

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Systematic deletions of E. coli genes that encode for membrane proteins demonstrate that the AcrAB-TolC efflux system is the major machinery responsible for intrinsic antibiotic resistance.

(A) Physical deletion of a resistance gene in a bacterium may render the bacterium antibiotic sensitive. (B) Representative MIC determination using final optical density at 600 nm (OD600) values at 22 h of incubation with the wild type (WT) E. coli and gene deletion mutants in increasing doses of clindamycin. The left vertical dashed line represents the MIC concentration for the acrB deletion mutant (magenta) while the right vertical dashed line represents the MIC for the remaining strains (WT and the cmr, emrB, marB, ompF deletion mutants). (C) Heat map showing the normalized mean MIC values for every strain, measured as in (B). MIC values were normalized using the wild type strain as the reference. All MIC measurements were run at least in duplicate and were found to be highly reproducible (S2B Fig). Relative change of the MIC (compared to WT) is depicted colorimetrically with blue representing statistically significant decreases (p < 0.05) in MIC and white representing nonsignificant changes in MIC. Intensity of the blue color indicates the magnitude of MIC change. MIC changes for only 11 of the 27 tested antibiotic compounds are shown here. The heat map for all antibiotics can be found in S2A Fig and the numerical MIC values can be found in S1 Table.

Fig 1

doi: https://doi.org/10.1371/journal.pbio.1002552.g001