Kim Group
Polyketide natural product biosynthesis • Antibiotic resistance • X-ray crystallography • Cryo-electron microscopy
We employ a structural biology-driven approach to elucidate two processes underlying bacterial natural product biosynthesis.
We are defining the enzymatic principles that govern the construction of polyketide natural products by dissecting the lasalocid A biosynthetic pathway. Lasalocid A, an ionophore polyketide antibiotic, exemplifies the modular logic of polyketide assembly and serves as a powerful model for deciphering polyketide biogenesis. Polyketides are a vital source of human therapeutics, having yielded antibiotics, anticancer agents, antifungal compounds, cholesterol-lowering drugs, and immunosuppressants. The remarkable structural diversity and broad pharmacological utility of polyketides underscore the importance of elucidating their biosynthetic mechanism.
In parallel, we are uncovering a unique self-resistance mechanism that enables echinomycin-producing bacteria to tolerate the cytotoxic effects of its own product. Echinomycin, a nonribosomal peptide natural product, is a DNA bisintercalator antibiotic that binds reversibly to DNA and blocks replication and transcription. This potent mode of action makes DNA bisintercalators compelling candidates for antimicrobial and anticancer drug development.
Together, these studies advance our fundamental understanding of natural product biosynthesis and resistance, laying the molecular foundation for next-generation antimicrobial and anticancer therapeutics.
We thank MRL (University of Illinois), SSRL (SLAC National Accelerator Laboratory), S2C2 (SLAC National Accelerator Laboratory), APS (Argonne National Laboratory), and ALS (Lawrence Berkeley National Laboratory) for instrumentation and technical support.
