Potentiation of Penicillin G and Selected β-Lactams with Quercetin Against Multidrug-Resistant Bacteria: Mechanistic Insights, Antibacterial Phytochemicals, and Toxicity Evaluation

Antimicrobial resistance is increasing, necessitating the development of novel and efficacious therapies. Plants contain phytochemicals, some of which may possess antibacterial properties. This research employed broth dilution experiments to investigate the antibacterial efficacy of fifteen phytochemicals identified in medicinal plant extracts. The sum of fractional inhibitory concentration of phytochemicals in conjunction with reference antibiotics were also analysed. The inhibitory effects of phytochemicals against β-lactamase were evaluated to explore their potential mechanisms of action. The phytochemicals were evaluated for toxicity on human dermal fibroblast cells. Gallic acid and luteolin significantly inhibited Staphylococcus aureus and the methicillin-resistant S. aureus (MRSA) strain, with minimum inhibitory concentration (MICs) of 62.5 µg/mL. Gallic acid also demonstrated restricted efficacy against Gram-negative species, with MICs ranging from 312.5 to 1250 µg/mL. Gram-negative bacteria exhibited no response to luteolin. Ellagic acid, catechin, naringenin, and quercetin exhibited moderate antibacterial efficacy against the tested pathogens (625–2500 µg/mL MIC). Corilagin exhibited significant antibacterial activity against S. aureus and MRSA, with a MIC of 7.81 µg/mL. Corilagin also exhibited notable efficacy against Bacillus cereus, Shigella flexneri, and Klebsiella pneumoniae, with MICs ranging from 62.5 to 250 µg/mL. Fractional inhibitory concentration studies revealed a synergistic effect between amoxicillin and corilagin against B. cereus. Additionally, catechin, luteolin, and quercetin synergised penicillin G against S. aureus. Quercetin potentiated the activity of β-lactams (amoxicillin, penicillin G, and oxacillin) against MRSA. Notably, these antibiotics were ineffective against MRSA alone. Isobologram analysis revealed potentiation between penicillin G and quercetin against MRSA at all tested ratios. The β-lactamase inhibitory activity of the phytochemicals was evaluated using a commercial screening kit, and the percentage of relative inhibition was determined. Quercetin and luteolin both inhibited β-lactamase, achieving relative inhibition rates of 77–100% across two time intervals. All phytochemicals were nontoxic against human dermal fibroblasts. Indeed, quercetin enhanced cell survival by 200%.