Synergism Between Krameria lappacea (Dombey) Burdet & B.B.Simpson Extracts and Gentamicin Against Gram-Positive Bacteria

Background: Combination therapy is increasingly explored as an alternative approach to manage bacterial infections and limit the emergence of antibiotic resistance. Building on traditional medicinal knowledge, this study aimed to investigate the potential synergistic antibacterial effects between Krameria lappacea (Dombey) Burdet & B.B.Simpson root extracts and conventional antibiotics. Methods: Root extracts were prepared using supercritical fluid extraction with different proportions of ethanol as a co-solvent. Their in vitro antibacterial activity was evaluated against Gram-positive bacteria and their interactions with gentamicin and vancomycin were assessed using an agar dilution-based combination assay. The chemical composition of the extracts was characterized using HRMS/MS-based dereplication and molecular networking. To further investigate the compounds contributing to the observed activity, an MS-guided isolation strategy was applied to an independent K. lappacea extract, resulting in the purification of a major neolignan previously detected in the active KL5 extract, which was subsequently evaluated using broth microdilution assays. Results: The less polar extract KL5, enriched in neolignans, exhibited the strongest antibacterial activity, with MIC values ranging from 3 to 12 µg/mL against Gram-positive strains. In combination assays, KL5 exhibited synergistic or additive interactions with gentamicin depending on the bacterial strain, whereas no synergistic effect was observed with vancomycin. The isolated neolignan displayed antibacterial activity and showed an additive interaction with gentamicin against Staphylococcus spp. Conclusions: These findings support the potential of K. lappacea neolignan-rich extracts as antibiotic adjuvants. The activity of the isolated neolignan supports the contribution of this chemical class to the antibacterial properties of KL5, while the absence of synergy for the isolated compound suggests that additional constituents and/or multicomponent interactions may contribute to the effect observed for the whole extract.