Discovery of Cladoescherins, Unusual Hybrid Metabolites Derived from a Fungal PKS and a Bacterial NRPS by Co-cultivation

Two novel macrolide hybrids, cladoescherins A and B (<b>1</b> and <b>2</b>), and a rare macrolide dimer, dithiocladospolide (<b>3</b>), were identified from cocultures of <i>Cladosporium</i> sp. and <i>Escherichia coli</i>. Compounds <b>1</b> and <b>2</b> feature a hybrid structural skeleton consisting of a 12-membered macrolide skeleton and a phenolate-thiazole-cysteine moiety. Compound <b>3</b> represents a rare example of symmetrical macrocyclic polyketide dimers connected by an intermolecular disulfide bridge. Biosynthetic study revealed that <b>1</b> and <b>2</b> were derived from the hybridization of the macrolide encoded by a fungal polyketide synthase (PKS) and the siderophore produced by a bacterial nonribosomal peptide synthetase (NRPS) via a spontaneous abiotic reaction. The discovery of cladoescherins reveals an unprecedented nonenzymatic inactivation of an exogenous electrophilic antibiotic by bacterial metabolite.