Background 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. Methods The 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. Results The 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. Conclusions The 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.

Infections caused by resistant pathogens result in significant morbidity and mortality and contribute to rising healthcare cost worldwide. The major mechanisms of resistance are permeability barrier of the outer membrane of Gram-negative bacteria as it slows down antibiotic entry into the periplasm. One approach to the restoration of antibiotic activity is to administer them in conjunction with non-antibiotic compounds that depress resistance mechanism. The present study aimed to study the effect of gallic acid, thymol, chitosan, sorbic acid, and EDTA on outer membrane permeability of irradiated and non-irradiated strains to enhance the activity of different antibiotics against multidrug resistance microorganisms. The plasmid profile analysis of some selected strains before and after irradiation was also determined. Various resistance rates were recorded for the tested antimicrobial agents. Percentage resistance of all the tested Gram-negative isolates to different beta-lactam antibiotics exceeded 50% in case of piperacillin (84.85%),cefoperazone / sulbactam (63.64%),cefoxitin (60.61%) while showed (100%) resistance in case of erythromycin.

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