<jats:title>Significance</jats:title> <jats:p>Leinamycin (LNM) is a promising anticancer drug lead, yet no analog has been isolated since its discovery nearly 30 y ago. By mining bacterial genomes, we discovered 49 potential producers of LNM-type natural products, the structural diversity of which was predicted based on bioinformatics and confirmed by in vitro characterization of selected enzymes and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity. New members of the LNM family of natural products should greatly facilitate drug discovery and development. The LNM-type biosynthetic machineries provide outstanding opportunities to dissect and mimic Nature’s strategies for combinatorial biosynthesis and natural product structural diversity.