Abstract
Antibiotic resistance is spreading at an alarming rate among pathogenic bacteria in both medicine and agriculture. Interfering with the intrinsic resistance mechanisms displayed by pathogenic bacteria has the potential to make antibiotics more effective and decrease the spread of acquired antibiotic resistance. Here, it is demonstrated that cranberry proanthocyanidin (cPAC) prevents the evolution of resistance to tetracycline in Escherichia coli and Pseudomonas aeruginosa, rescues antibiotic efficacy against antibiotic‐exposed cells, and represses biofilm formation. It is shown that cPAC has a potentiating effect, both in vitro and in vivo, on a broad range of antibiotic classes against pathogenic E. coli, Proteus mirabilis, and P. aeruginosa. Evidence that cPAC acts by repressing two antibiotic resistance mechanisms, selective membrane permeability and multidrug efflux pumps, is presented. Failure of cPAC to potentiate antibiotics against efflux pump‐defective mutants demonstrates that efflux interference is essential for potentiation. The use of cPAC to potentiate antibiotics and mitigate the development of resistance could improve treatment outcomes and help combat the growing threat of antibiotic resistance.
Highlights
To cite this version: Vimal Maisuria, Mira Okshevsky, Eric Déziel, Nathalie Tufenkji
fractional inhibitory concentration index (FICI) values of ≤0.5 demonstrate that cranberry proanthocyanidin (cPAC) potentiated the effectiveness of sulfamethoxazole (SMX), nitrofurantoin (NIT), gentamicin (GEN), kanamycin (KAN), tetracycline (TET), and azithromycin (AZT) to inhibit the growth of E. coli CFT073, P. mirabilis HI4320, and P. aeruginosa PA14 using up to 98% less antibiotic than that required in the absence of cPAC. cPAC potentiated trimethoprim (TMP) and fosfomycin (FOS) activities to inhibit the growth of P. mirabilis HI4320; 81% and 98% less antibiotic were needed, respectively, than in the absence of cPAC
Investigations into efflux pump activity using ethidium bromide (EtBr) as a fluorescent indicator substrate showed that, in contrast to the decay in fluorescence observed in untreated cells (Figure 5D–F), cells treated with cPAC, or the efflux pump inhibitor carbonyl cyanide m-chlorophenylhydrazone (CCCP), remained fluorescent over time due to a failure to pump out EtBr (Figure 5D–F)
Summary
We conducted screening assays with cPAC in combination with several classes of clinically approved antibiotics belonging to the World Health Organization’s list of essential medications.[27]. Similar effects were observed with minocycline (MIN; Figure S4, Supporting Information) against E. coli CFT073 These results suggest that cPAC can prolong the efficacy of remnant antibiotic against antibiotic-exposed cells even after treatment has ceased. Our goal was to investigate the potential of cPAC to enhance the efficacy of antibiotics against bacterial infections in vivo To this end, we used the model host Drosophila melanogaster infected with P. aeruginosa PA14, in which cPAC or SMX was administered alone or in combination. As with the D. melanogaster feeding assay, there was no difference in survival curves of uninfected G. mellonella larvae with or without treatment of cPAC or SMX alone (Figure S5B, Supporting Information) These results confirm that cPAC potentiates the activity of SMX in vivo, at the tested concentration of 50 μg mL−1 cPAC. Because a combination of cPAC and SMX is more effective against biofilms than either compound is alone, these observations demonstrate that cPAC acts synergistically with SMX to reduce the ability of bacteria to form biofilms, and supports the hypothesis that cPAC contributes to the impairment of dormant antibiotic-exposed cells
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