Chejuenolide D, an Anti-inflammatory 17-Membered Macrocyclic Polyketide from an iChip-Domesticated Marine Bacterium Hahella sp. NBU794

Background The strategy of an isolation chip (iChip) can enhance discovery of uncultured microorganisms with the potential to produce new bioactive natural products. Additionally, genome mining and NMR spectra features analysis have been effective methods to search for new target molecule. Macrocyclic polyketides with a 17-membered carbocyclic ring system were reportedly rare and our undertaking enriched the compound family as well as bioactivity of 17-membered macrocyclic polyketides. Results In this study, guided by genome mining and HSQC-based Small Molecule Accurate Recognition Technology (SMART), a new macrocyclic polyketide with a 17-membered carbocyclic ring system, chejuenolide D ( 1 ), together with a known analog, chejuenolide A ( 2 ), were obtained from an organic extract of Hahella sp. NBU794 isolated by using an iChip for high-throughput in situ cultivation. The planar structures and absolute configurations of these compounds were elucidated by detailed spectroscopic analysis, the modified Mosher’s method, quantum chemical calculation and X-ray single crystal diffraction. In our antibacterial assay against S. aureus and B. subtilis , compound 1 and 2 showed no antibacterial bioactivity. However, compound 1 showed notable Cyclooxygenase-2 (COX-2) inhibitory activity (IC ₅₀  = 3.87 µM) in the anti-inflammatory evaluation. Conclusions This study was the first to report a new 17-membered macrocyclic polyketide chejuenolide D ( 1 ) with anti-inflammatory from uncultured microorganism Hahella sp. NBU794 combining genome mining and SMART. These results not only displayed the significance of searching uncultured microorganism using iChip technology but also provided a valuable reference for future exploration of macrocyclic polyketide compounds as well as target drug discovery.