Phytocompounds from Terminalia brownii Fresen. Bark target bacterial DHFR: An integrated In vitro, In silico, and In...

Terminalia brownii Fresen. is widely used in East African traditional medicine for treating infectious diseases, especially diarrhea and dysentery. However, there is limited scientific evidence supporting its antimicrobial efficacy and safety.

To evaluate the antibacterial activity, phytochemical constituents, potential mechanisms of action, and in vivo safety of the aqueous bark extract of T. brownii, with a focus on validating its traditional use and identifying bioactive compounds targeting Gram-negative pathogens.

Antibacterial activity was assessed against eight Gram-negative bacterial strains using disk diffusion and broth microdilution methods. LC-MS was employed to identify phytochemicals. In silico docking and molecular dynamics simulations examined compound interactions with E. coli dihydrofolate reductase (DHFR), alongside ADMET prediction using SwissADME. Sub-acute toxicity was evaluated in male Swiss albino mice over 28 days (OECD guideline 407), with analysis of body and organ weights, haematological, and biochemical parameters.

The extract exhibited strong antibacterial effects, notably against Shigella flexneri and S. sonnei. MIC and MBC values ranged from 3.125 to 100 mg/ml; K. pneumoniae showed limited susceptibility. LC-MS identified catechin, lupeol, and naringenin as major bioactive compounds. These showed high DHFR binding affinities, stable molecular dynamics profiles, and favorable ADMET characteristics. In vivo studies revealed no significant toxicity at doses ≤630 mg/kg, though mild hepatic and renal effects were observed at 1000 mg/kg.

These findings validate the traditional use of T. brownii and highlight its potential as a source of DHFR-inhibiting antibacterial agents for integration into modern antimicrobial strategies.