The rising threat of Multidrug-Resistant Tuberculosis (MDR-TB), caused by Mycobacterium tuberculosis (Mtb), underscores the urgent need for new therapeutic solutions to tackle the challenge of antibiotics resistance. The current study utilized an innovative 3R infection model featuring the amoeba Dictyostelium discoideum infected with Mycobacterium marinum, serving as stand-ins for macrophages and Mtb, respectively. This high-throughput phenotypic assay allowed for the evaluation of more specific anti-infective activities that may be less prone to resistance mechanisms. To discover novel anti-infective compounds, a diverse collection of 1,600 plant extracts from the Pierre Fabre Library (PFL) was screened using the latter assay. Concurrently, these extracts underwent untargeted UHPLC-HRMS/MS analysis. The biological screening flagged the extract from Stauntonia brunoniana as one of the anti-infective hit extracts. High-resolution HPLC micro-fractionation coupled with bioactivity profiling was employed to highlight the natural products (NPs) driving this bioactivity. Stilbenes were eventually identified as the primary active compounds in the bioactive fractions. A knowledge graph (KG) was then used to leverage the heterogeneous data integrated into it to make a rational selection of stilbene-rich extracts. Using both CANOPUS chemical classes and Jaccard similarity indices (JSIs) to compare features within the metabolome of the 1600 NEs set, 14 extracts rich in stilbenes were retrieved. Among those, the roots of Gnetum edule were flagged as possessing broader chemo-diversity in their stilbene content, along with the corresponding extract also being a strict anti-infective. Eventually, a total of 11 stilbene oligomers were isolated from G. edule and fully characterized by NMR with their absolute stereochemistry established through electronic circular dichroism (ECD). Six of these compounds are new since they possess a stereochemistry which was never described in the literature to the best of our knowledge. All of them were assessed for their anti-infective activity and (-)-Gnetuhainin M was reported as having the highest anti-infective activity with an IC50 of 22.22 μM.