Combretum species exhibit potent antibacterial and antifungal properties, but limited studies exist for most species. This study reports for the first time the in vitro antimicrobial and antibiofilm activities of Combretum platypetalum leaf, stem, and root. Fungi and bacterial strains implicated in the causes of some of the conditions to which C. platypetalum is traditionally applied were evaluated by Agar-well diffusion and micro-dilution methods, and their biofilm inhibition capacities were investigated. The highest zone of fungal inhibition of 22.70 ± 2.08 mm against C. albicans and the highest zone of bacterial inhibition of 21.70 ± 2.08 mm against S. aureus were observed. The minimum inhibitory concentration (MIC) ranged between 0.0156 mg/mL and 8.0000 mg/mL for fungi and 0.3906 mg/mL and 8.0000 mg/mL for bacteria at P = 0.0002. The best minimum fungicidal concentrations (MFCs), at P = 0.003, were observed at 0.0630 mg/mL for the leaf against C. glabrata and C. neoformans and 0.5 mg/mL for the root against C. neoformans, respectively. The highest biofilm inhibition of 40.61%, 36.04%, and 23.85% was observed in the stem, root, and leaf extracts against C. glabrata. Chloroform leaf extract reveals ?-sitosterol as the active antifungal and antibacterial agent. Computational antifungal activity and molecular docking analysis of the structure versus target (sterol 14?- demethylase) show a binding affinity for druggability. The leaves and roots are the most potent parts of the plant, with leaf extracts showing non-synergistic effects. Bioguided isolation is recommended to fully explore the species' evidence-based therapeutic potential.

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