SCRIPPS INSTITUTION OF OCEANOGRAPHY FACULTY CANDIDATE SEMINAR: Human Health and the Oceans
DATE: April 20th, Friday, 10:00 a.m.
LOCATION: Eckart Lecture Hall
SPEAKER: Kerry McPhail, Ph.D.
Oregon State University
TITLE: Genomics-Assisted Microbial Natural Products Discovery and Inhibition of Protein Secretion
The dominant role of “privileged” natural product (NP) structures in modern medicine is well established, especially for microbial NPs in the treatment of infectious diseases and cancers. Many microbial NP-based drugs have arisen from serendipitous discoveries involving relatively limited chemical and biological screening, followed by lengthy development paths for unanticipated indications. The discovery of extensive NP biosynthetic potential in sequenced microbial genomes, has prompted efforts to target biosynthetic genes for known NPs in short supply for structure elucidation or biological investigations, or that potentially represent new chemical entities with new biological mechanisms but remain “cryptic”. We have taken advantage of collaborations in metagenomics and pharmacology to facilitate our investigations of new NP structures from marine tunicate/microbial symbiont consortia, and microbial communities dominated by cyanobacteria. In addition, a collaboration with evolutionary biologists investigates the evolutionary patterns and processes of NP diversification in ecologically diverse hypocrealean fungi by linking genomics, transcriptomics and secondary metabolomics. This systematic study to explore biologically active NP production in an evolutionary and ecological context may provide a predictive framework for specific human health applications. After discovery of cyclic depsipeptide coibamide A as a substrate-selective inhibitor of cellular protein secretion, we have used whole-cell mechanism-based assays for the discovery of additional inhibitors and investigation of the structural basis for substrate-selective inhibition. Cyanobacteria, fungi and tunicate consortia produce nonpolar cyclic depsipeptides consistent with the handful of known inhibitors of the protein secretory pathway, which is an emerging therapeutic target due to its central involvement in regulating cellular proteostasis and protein folding, and its dysregulation in human disease.
Faculty Host: Brad Moore (firstname.lastname@example.org)