Natural product reisolation is a bottleneck when discovering new bioactive chemical entities from nature. To overcome this issue, multi-informative approaches integrating several layers of data have been applied with promising results. In this study, integration of taxonomy, nontargeted metabolomics, and bioactivity information resulted in the selection of Scytalidium sp. IQ-074 and Diaporthe sp. IQ-053 to isolate new natural products active against hPTP1B_1–400 and repurpose others as antibiotics. Strain IQ-074 was selected based on the hypothesis that investigating poorly studied and highly metabolic taxa could lead to the isolation of new chemical entities. A chemical investigation of IQ-074 resulted in the isolation of papyracillic acid A (14), 7-deoxypapyracillic acid A (15a and 15b), and linear polyketides scytalpolyols A–D (16–19). Compound 17 inhibited hPTP1B_1–400 with a half-maximal inhibitory concentration of 27.0 ± 1.7 μM. Diaporthe sp. IQ-053 was selected based on its antibacterial properties against pathogenic strains. Its chemical investigation yielded dothiorelones A (20) and I (21), cytosporones B (22) and C (23), pestalotiopsone B (24), and diaporthalasin (25). Compounds 22 and 25 inhibited the growth of Staphylococcus aureus and Staphylococcus epidermidis 42R and moderately inhibited the growth of Acinetobacter baumannii A564, a pandrug-resistant bacterium.