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 (1 and 2), and a rare macrolide dimer, dithiocladospolide (3), were identified from cocultures of Cladosporium sp. and Escherichia coli. Compounds 1 and 2 feature a hybrid structural skeleton consisting of a 12-membered macrolide skeleton and a phenolate-thiazole-cysteine moiety. Compound 3 represents a rare example of symmetrical macrocyclic polyketide dimers connected by an intermolecular disulfide bridge. Biosynthetic study revealed that 1 and 2 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.