Microbial Pathogenesis; Microbiology; Protein Function and Structure; Proteins and metalloenzymes; Structural Biology; X-ray Crystallography
My research program aims to understand how bacteria produce natural products, small molecules that are secreted from the cell to adapt to diverse environments. These molecules allow the bacteria to compete with other microbes or, in the host-pathogen setting, to establish or exacerbate an infection. Natural product biosynthesis may therefore serve as a target for antimicrobial development.
My lab uses a variety of techniques to examine these pathways. A core approach is to use X-ray crystallography to determine the molecular structure of proteins that catalyze important steps in natural product biosynthesis. Structural observations are tested and validated using biochemical techniques to examine the catalytic reactions. Finally, molecular and cellular techniques are used to examine biosynthetic gene cluster activity in the cell. These studies will inform efforts to engineer enzymes to produce novel natural product and identify new products of previously uncharacterized pathways.
I have a long-standing interest in the Nonribosomal Peptide Synthetases (NRPSs), a family of large, multidomain enzymes that produce important peptide natural products like the antibiotic vancomycin or the anticancer agent bleomycin. NRPSs operate like an assembly line in which the nascent peptide is attached to a carrier domain that shuttles the synthetic intermediates to neighboring catalytic domains. The carrier and catalytic domains are often joined in a single polypeptide that is thousands of residues in length. By examine the crystal structures of large NRPS proteins, we have determined some of the features that enable this fascinating biosynthetic mechanism.
Many NRPS products are siderophores, small molecules that bind iron and are required for growth in the pathogenic environment. My lab also studies aerobactin, an NRPS-independent siderophore pathway that is a virulence factor for hypervirulent Klebsiella pneumoniae. We have biochemically and structurally characterized the aerobactin biosynthetic pathway and have developed an approach to find inhibitors of aerobactin biosynthesis that may be tools to probe the pathway chemically to inhibit growth of this human pathogen.