Uncommon organisms adapted to specific habitats and at habitat interfaces are rational sources of specialized metabolites with important biological properties related to the ecology and evolution of these organisms. The McPhail Lab is interested in characterizing macrocyclic natural products, for example, from insect-associated fungi, cyanobacteria, sea squirts and salamander microbiomes, that may serve as biomedical research tools or starting points for new disease treatments.

We use two distinct approaches for natural products chemistry:

• Chromatographic isolation and structure elucidation of new natural products, using NMR spectroscopy, mass spectrometry, and chemical degradation/derivatization, and guided by biological activity testing.
• Untargeted metabolomics using LCMS/MS for comparative computational analyses of limited environmental samples, and integration with genomic sequence data.

Our specific projects include working with an internationally collaborative group to characterize microbial macrocycles, such as coibamide A, that inhibit the Sec61 translocon or regulate protein translation by interacting with the ribosomal nascent complex as molecular glues. As much as 40% of the human proteome are secreted or membrane proteins that are synthesized at the endoplasmic reticulum (ER), and potentially dysregulated in chronic diseases. Organisms such as cyanobacteria, fungi and human pathogenic bacteria produce inhibitors of the Sec61 protein translocon complex, which translocates a majority of secreted and membrane proteins across the ER membrane during their initial biogenesis.

A second nationally collaborative project (https://herptilemicrobiomes.org/) investigates the herptile gut microbiome with the aim of demonstrating that the animal gut promotes horizontal gene transfer (HGT) between bacteria and fungi, and that this HGT selects for specific metabolites that function in microbial interactions in native microbiomes.