Integrating Taxonomic and Chemical Diversity of Mangrove-Associated Ascomycetes to Discover or Repurpose Bioactive Natural Products.

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 hPTP1B1-400 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 hPTP1B1-400 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.

Absolute configuration and protein tyrosine phosphatase 1B inhibitory activity of xanthoepocin, a dimeric naphtopyrone from Penicillium sp. IQ-429.

Protein tyrosine phosphatase 1B (PTP1B) is an active target for developing drugs to treat type II diabetes, obesity, and cancer. However, in the past, research programs targeting this enzyme focused on discovering inhibitors of truncated models (hPTP1B1-282, hPTP1B1-298, or hPTP1B1-321), losing valuable information about the ligands' mechanism of inhibition and selectivity. Nevertheless, finding an allosteric site in hPTP1B1-321, and the full-length (hPTP1B1-400) protein expression, have shifted the strategies to discover new PTP1B inhibitors. Accordingly, as part of a research program directed at finding non-competitive inhibitors of hPTP1B1-400 from Pezizomycotina, the extract of Penicillium sp. (IQ-429) was chemically investigated. This study led to xanthoepocin (1) isolation, which was elucidated by means of spectroscopic and spectrometric data. The absolute configuration of 1 was determined to be 7R8S9R7'R8'S9'R by comparing the theoretical and experimental ECD spectra and by GIAO-NMR DP4 + statistical analysis. Xanthoepocin (1) inhibited the phosphatase activity of hPTP1B1-400 (IC50 value of 8.8 ± 1.0 µM) in a mixed type fashion, with ki and αki values of 5.5  and 6.6 µM, respectively. Docking xanthoepocin (1) with a homologated model of hPTP1B1-400 indicated that it binds in a pocket different from the catalytic triad at the interface of the N and C-terminal domains. Molecular dynamics (MD) simulations showed that 1 locks the WPD loop of hPTP1B1-400 in a closed conformation, avoiding substrate binding, products release, and catalysis, suggesting an allosteric modulation triggered by large-scale conformational and dynamics changes. Intrinsic quenching fluorescence experiments indicated that 1 behaves like a static quencher of hPTP1B1-400 (KSV = 1.1 × 105 M-1), and corroborated that it binds to the enzyme with an affinity constant (ka) of 3.7 × 105 M-1. Finally, the drug-likeness and medicinal chemistry friendliness of 1 were predicted with SwissADME.