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.