Site-Specific Introduction of Sulfoxides and Sulfones into Polyketide Scaffolds through a Relayed Chemo-Biosynthetic Strategy

Abstract

Sulfoxides and sulfones are pivotal pharmacophores and versatile functional groups in drug design; however, they are rarely found in natural products. In this study, we developed a chemo-biosynthetic strategy for the site-specific introduction of sulfoxides and sulfones into polyketide frameworks. This method involves integrating hydrophobic sulfide-extender units into the polyketide structure, followed by sequential oxidation with hydrogen peroxide to convert the sulfides into polar sulfoxides and sulfones. This approach addresses the challenge that polar groups face in being recognized by the natural hydrophobic pockets of biosynthetic enzymes. The sulfide-extender units were synthesized using a permissive acyl-CoA synthetase (UkaQ^FAV) and an acyl-CoA carboxylase (Arm13-ACC), which is specific to medium- to long-chain acyl-CoA substrates. The crystal structure of Arm13 was resolved to 1.6 Å, enabling the development of the mutant Arm13^V157I, which exhibits significantly enhanced catalytic efficiency for short-chain acyl-CoA substrates. By incorporating these units into a deacyl antimycin (DA)-producing strain and feeding it sulfur-containing substrates, followed by oxidation, we successfully generated nine representative sulfone and sulfoxide-DAs. This work not only paves the way for the development of sulfur-containing polyketides but also provides an effective strategy for introducing polar functionalities into polyketide frameworks.