Exploring synergistic potential of phytomolecules-antibiotics combination against Escherichia coli: An integrated approach using structure based drug design

Abstract

The rise of antibiotic-resistant Escherichia coli (E. coli), a pathogen responsible for conditions like urinary tract infections, sepsis, and gastroenteritis, presents a critical challenge to public health, necessitating innovative therapeutic strategies. This study investigates the potential of phytomolecules as adjuncts to conventional antibiotics in combating E. coli resistance. Natural compounds, despite their critical role in drug discovery, often lack sufficient potency against resistant bacteria when used alone. However, in combination with antibiotics, they can create a synergistic effect, enhancing antibacterial efficacy and mitigating the risk of further resistance. Our research involved virtual screening of diverse small molecules against key E. coli targets, including PBP2, PBP3, Topoisomerase IV subunits A and B, Extended Spectrum β-lactamase, MurA, and DHFR. Phytomolecules such as thymol, eugenol, xanthohumol, brazilin, quercetin, curcumin, and berberine were identified as promising candidates based on their docking scores, binding free energy, and interactions. These were further assessed for ADMET and drug-likeness properties using pkCSM, SwissADME, and QikProp tools. In vitro testing against E. coli revealed xanthohumol as particularly potent, with a minimum inhibitory concentration (MIC) of 7.8 μg/ml. Other molecules, including berberine, citral, thymol, and curcumin, showed MICs ranging from 62.5 to 250 μg/ml, while quercetin and eugenol had MICs between 500 and 1000 μg/ml. Notably, xanthohumol exhibited strong synergy with ampicillin, underscoring its significant antibacterial potential. These results suggest that phytomolecule-antibiotic combinations could serve as a novel approach to enhance the efficacy of existing antibiotics, providing a promising solution to the growing challenge of E. coli antibiotic resistance.