Site-Specific Introduction\nof Sulfoxides and Sulfones\ninto Polyketide Scaffolds through a Relayed Chemo-Biosynthetic Strategy

Sulfoxides and sulfones are pivotal pharmacophores and\nversatile\nfunctional groups in drug design; however, they are rarely found in\nnatural products. In this study, we developed a chemo-biosynthetic\nstrategy for the site-specific introduction of sulfoxides and sulfones\ninto polyketide frameworks. This method involves integrating hydrophobic\nsulfide-extender units into the polyketide structure, followed by\nsequential oxidation with hydrogen peroxide to convert the sulfides\ninto polar sulfoxides and sulfones. This approach addresses the challenge\nthat polar groups face in being recognized by the natural hydrophobic\npockets of biosynthetic enzymes. The sulfide-extender units were synthesized\nusing a permissive acyl-CoA synthetase (UkaQ<sup>FAV</sup>) and an\nacyl-CoA carboxylase (Arm13-ACC), which is specific to medium- to\nlong-chain acyl-CoA substrates. The crystal structure of Arm13 was\nresolved to 1.6 Å, enabling the development of the mutant Arm13<sup>V157I</sup>, which exhibits significantly enhanced catalytic efficiency\nfor short-chain acyl-CoA substrates. By incorporating these units\ninto a deacyl antimycin (DA)-producing strain and feeding it sulfur-containing\nsubstrates, followed by oxidation, we successfully generated nine\nrepresentative sulfone and sulfoxide-DAs. This work not only paves\nthe way for the development of sulfur-containing polyketides but also\nprovides an effective strategy for introducing polar functionalities\ninto polyketide frameworks.