Abstract
BackgroundThis study sought to develop new strategies for reverting the resistance of pathogenic Gram-negative bacilli by a combination of conventional antibiotics, potent permeabilizers and natural beta lactamase inhibitors enhancing the activity of various antibiotics.MethodsThe antibiotic susceptibility in the presence of natural non-antibacterial tested concentrations of phytochemicals (permeabilizers and natural beta lactamase inhibitors) was performed by disk diffusion and susceptibility assays. Thymol and gallic acid were the most potent permeabilizers and facilitated the passage of the antibiotics through the outer membrane, as evidenced by their ability to cause LPS release, sensitize bacteria to SDS and Triton X-100.ResultsThe combination of permeabilizers and natural beta lactamase inhibitors (quercetin and epigallocatechin gallate) with antibiotics induced greater susceptibility of resistant isolates compared to antibiotic treatment with beta lactamase inhibitors alone. Pronounced effects were detected with 24.4 Gy in vitro gamma irradiation on permeability barrier, beta lactamase activity, and outer membrane protein profiles of the tested isolates.ConclusionsThe synergistic effects of the studied natural phytochemicals and antibiotics leads to new clinical choices via outer membrane destabilization (permeabilizers) and/or inactivation of the beta lactamase enzyme, which enables the use of older, more cost-effective antibiotics against resistant strains.
Highlights
This study sought to develop new strategies for reverting the resistance of pathogenic Gram-negative bacilli by a combination of conventional antibiotics, potent permeabilizers and natural beta lactamase inhibitors enhancing the activity of various antibiotics
These concentrations [gallic acid (≤ 600 μg/mL), ellagic acid (≤ 40 μM), thymol (≤ 500 μg/mL), chitosan (≤ 100 ppm), Ethylenediaminetetraacetic acid (EDTA) (≤ 0.1 mM), and sorbic acid (≤ 5 mM)] were selected for further studies to guarantee that any inhibitory effect and antibacterial activity would be due to the antibiotic action alone and ensure that the permeabilizers had no inherent antibacterial activity
The results obtained in the current study revealed that, for the 10 non-beta lactamase producing isolates, gallic acid and thymol were the most potent permeabilizers—
Summary
This study sought to develop new strategies for reverting the resistance of pathogenic Gram-negative bacilli by a combination of conventional antibiotics, potent permeabilizers and natural beta lactamase inhibitors enhancing the activity of various antibiotics. Permeabilizers are compounds that weaken the OM and can nonspecifically enhance the permeability of bacterial cells to exogenous products, including antimicrobial agents. They may potentiate the antibacterial activity of antibiotics that interact with intracellular targets mainly due to the perturbation of the lipid fraction of the cell membrane as they disintegrate the LPS layer. Owing to their lipophilic character, they can increase membrane permeability.
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