In silico docking and pharmacokinetic evaluation of African ethnomedicinal phytochemicals as dual-target inhibitors of multidrug-resistant Gram-negative bacteria

Abstract

The emergence of multidrug-resistant (MDR) Gram-negative bacteria, including Escherichia coli and Pseudomonas aeruginosa, poses a critical global health challenge, necessitating innovative antimicrobial strategies. Leveraging Africa’s rich phytochemical diversity, this study integrates molecular docking and in silico pharmacokinetic profiling to identify natural compounds with dual-target potential. Ten bioactive phytochemicals from ethnomedicinal plants were screened against four validated bacterial targets: LasR (2UV0), AcrB efflux pump (5NC5), DNA gyrase B (6F86), and TEM-1 β-lactamase (1BTL) with AutoDock Vina implemented in PyRx, and the resulting protein-ligand interactions analyzed in Discovery Studio. Docking identified luteolin as exhibiting the highest binding affinity for LasR (−10.8 kcal/mol) and TEM-1, indicating dual inhibition of quorum sensing and β-lactamase activity. Rutin (−9.2 kcal/mol) exhibited high affinity for AcrB, indicating potential efflux pump inhibition, while ellagic acid (−8.3 kcal/mol) targeted DNA gyrase, potentially impairing bacterial replication. Absorption, distribution, metabolism, excretion, and toxicity analyses, along with ProTox-3 predictions, indicated that luteolin exhibited high gastrointestinal absorption and moderate systemic toxicity. Ellagic acid exhibited excellent biocompatibility, whereas rutin showed favorable drug-likeness but low permeability. Collectively, luteolin, rutin, and ellagic acid emerged as promising computational leads with complementary inhibitory mechanisms. This study highlights the translational potential of African phytochemical scaffolds in rational, computer-aided antimicrobial design and provides a foundation for subsequent in vitro and in vivo validation toward novel anti-MDR therapeutics.

Keywords

Luteolin / Rutin / Ellagic acid / Multidrug resistance / Gram-negative bacteria / Molecular docking / ADMET / African medicinal plants

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