Bipentaromycins are heterodimeric aromatic polyketides featuring two distinctive 5/6/6/6/5 pentacyclic ring systems and exhibit antibacterial activities. However, their overall biosynthetic mechanism, particularly the mechanism for early-stage modifications, such as hydrogenation and methylation, and late-stage dimerization, remains unknown. Herein, by integrating heterologous expression, isotope labeling, gene knockout and complementation, and computational modeling, we determined the biosynthetic origin of the skeleton, identified the enzymes involved in stereo-/regioselective hydrogenation and methylation, and provided new mechanistic insights into the dimerization. This work not only deciphers the biosynthetic mechanism of bipentaromycins but also provides new strategies for creating biologically active dimeric pharmacophores for drug discovery and development.
© 2022 The Authors. Published by American Chemical Society.