Insights into the Biosynthesis of Kibdelomycin and Amycolamicin from Comparative Biosynthetic Gene Cluster Analysis and Precursor Incorporation Studies.

Kibdelomycin and amycolamicin are identical antibiotics produced by Kibdelosporangium banguiense CA-240109 and Amycolatopsis sp. MK575-fF5, respectively. They are broad-spectrum antibiotics showing potent activity against antibiotic-resistant Gram-positive bacteria. These compounds inhibit DNA gyrase subunit B (GyrB) and topoisomerase IV (ParE) by a unique U-shaped multicontact binding mode and have no cross-resistance to known antibiotics. Kibdelomycin represents a promising scaffold for developing new antibiotics, but its poor production, structural complexity, and chemical stability limit its chemical modification. In this work, we describe the improvement of kibdelomycin production via strain mutagenesis and the elucidation of kibdelomycin biosynthesis using isotope-labeled feeding experiments and sequencing of the kibdelomycin and amycolamicin biosynthetic gene clusters (BGCs), which are similar but not identical. These studies provide avenues for structure-guided biosynthetic analogue development as well as material for chemical modification.