Antibacterial efficacy and bioisosteric optimization of lead compounds from tithonia diversifolia targeting DNA gyrase B in multidrug-resistant bacteria

The clinical utility of antibiotics is increasingly threatened by the rise of multidrug-resistant bacteria. As resistance undermines current therapies, interest has shifted toward plant-derived natural products. This study evaluated the antibacterial efficacy of crude and fractionated leaf extracts of Tithonia diversifolia against selected multidrug-resistant strains. Molecular docking and bioisosteric replacement approaches were also employed to identify and optimize lead phytocompounds targeting bacterial DNA gyrase-B. Phytochemical extraction was performed by maceration, followed by liquid–liquid fractionation. Antibacterial activity was assessed via agar well diffusion, and minimum inhibitory/bactericidal concentrations (MIC/MBC) values were determined using standard dilution and plating methods. High performance liquid chromatography (HPLC) was used for phytochemical profiling. Selected compounds were docked against DNA gyrase-B of E. coli (7C7N), A. baumannii (7PQM), and S. aureus (3G75), and bioisosteric analogues were evaluated for improved activity. The crude extract showed the highest activity against E. coli (17.50 ± 0.58 mm), while the most active fraction inhibited P. aeruginosa (17.33 ± 0.33 mm). MIC values ranged from 3.125 to 12.5 mg/ml. HPLC revealed key constituents including epicatechin, quercetin, eugenol, curcumin, and limonene. Epicatechin (–6.734 kcal/mol) and quercetin (–6.720 kcal/mol) showed the strongest binding affinities, outperforming novobiocin. All lead compounds met drug-likeness and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) standards. Bioisosteres like Epicatechin 7a (–8.026 kcal/mol) and Quercetin 6 (–7.210 kcal/mol) exhibited enhanced interactions. Conclusively, T. diversifolia harbors promising antibacterial agents, with epicatechin and quercetin showing strong inhibitory potential against DNA gyrase-B. These findings support further development of its phytochemicals as candidates for managing multidrug-resistant infections.