McPhail Kerry

Kerry Mcphail, PhD

Academic Information

Departments College of Pharmacy , Professor and Chair - Medicinal Chemistry

Academic Office Information

kerry.mcphail@pharm.utah.edu

801-585-7269

Lab

Research Interests

  • Natural products (NP) drug discovery using microbial macrocycles
  • Untargeted metabolomics based on tandem mass spectrometry
  • ‘Large small molecule’ inhibitors of protein synthesis and secretion
  • Horizontal gene transfer and NP expression in herptile microbiomes

RESEARCH DESCRIPTION

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:

  1. Chromatographic isolation and structure elucidation of new natural products, using NMR spectroscopy, mass spectrometry, and chemical degradation/derivatization, and guided by biological activity testing.

  2. 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 microbiome.

RELATED LINKS

FAR Webpage

College of Pharmacy

Education History

Postdoctoral Training Oregon State University
Rhodes University
Chemistry 		PhD
Undergraduate Rhodes University
Chemistry and Marine Biology 		BS Hons

Selected Publications

Journal Article

  1. Avalon, N.E.,* Reis, M.A.,* Thornburg, C.C.,* Williamson, R.T., Petras, D, Aron, A.T…McPhail, K.L., Gerwick, W.H. et al. Leptochelins A-C, Cytotoxic Metallophores Produced by Geographically Dispersed Leptothoe Strains of Marine Cyanobacteria. J. Am. Chem. Soc. 2024, 146, 27: 18626–18638.

  2. Neuhaus, G.F., Aron, A.T., Isemonger, E.W., Petras, D., Waterworth, S.C., Madonsela, L.S., Gentry, E.C., Siwe Noundou, X., Kalinski, J-C.J., Polyzois, A., Habiyaremye, J.C., Redick, M.A., Kwan, J.C., Dorrington, R.A., Dorrestein, P.C., McPhail, K.L. Environmental metabolomics characterization of modern stromatolites and annotation of ibhayipeptolides. PLoS ONE 2024, 19(5): e0303273. https://doi.org/10.1371/journal.pone.0303273.

  3. Mattos, D.R., das Neves, W., Kitamura, T., Pradhan, R., Wan, X., da Hora, C.C., Tranter, D., Kazemi, S., Yu, X., Tripathy, N., Paavilainen, V.O., McPhail, K.L., Oishi, S., Badr, C.E., Ishmael, J.E. Diastereomers of Coibamide A show altered Sec61 Client Selectivity and Ligand-Dependent Activity against Patient-derived Glioma Stem-Like Cells. ACS. Pharmacol. Translation. Sci. 2024, 7(6): 1823–1838.

  4. Vargas-Gastélum, L., Romer, A.S., Alexander, N.R., Ghotbi, M., Dallas, J.W., Alexander, N.R., Moe, K.C., McPhail, K.L., Neuhaus, G.F., Shadmani, L., Spatafora, J.W., Stajich, J.E., Tabima, J.F., Walker, D.M. Herptile gut microbiomes: a natural system to study multi-kingdom interactions between filamentous fungi and bacteria. mSphere, 2024. 9:e00475-23. Doi: 10.1128/msphere.00475-23.

  5. Redick, M.A., Cummings, M.E., Neuhaus, G.F., Ardor Belluci, L.M., Thurber, A.R., McPhail, K.L. Integration of Untargeted Metabolomics and Microbial Community Analyses to Characterize Distinct Deep-Sea Methane Seeps. Frontiers in Marine Science, 2023, 10: 1197338. Doi: 10.3389/fmars.2023.1197338.

  6. Suzuki, R., Mattos, D.R., Kitamura, T., Tsujioka, R., Kobayashi, K., Inuki, S., Ohno, H., Ishmael, J.E., McPhail, K.L., Oishi, S. Design of Synthetic Surrogates for the Macrolactone Linker Motif in Coibamide A. ACS Med. Chem. Lett. 2023, 14:1344–1350.

  7. Tehan, R.M., Dooley, C.B., Barge, E.G., McPhail, K.L., Spatafora, J.W. New species and new combinations in the genus Paraisaria (Hypocreales, Ophiocordycipitaceae) from the U.S.A., supported by polyphasic analysis. Mycokeys 2023, 100: 69-94.

  8. Tehan, R.M.; Blount, R.R.; Goold, R.L.; Mattos, D.R.; Spatafora, N.R.; Tabima, J.F.; Gazis, R.; Wang, C.; Ishmael, J.E.; Spatafora, J.W.; McPhail, K.L. Tolypocladamide H and the Proposed Tolypocladamide NRPS in Tolypocladium Species. Journal of Natural Products. 2022, 85: 1363-1373.

  9. Kitamura, T.; Suzuki, R.; Inuki, S.; Ohno, H.; McPhail, K.L.; Oishi, S. Design of coibamide A mimetics with improved cellular bioactivity. ACS Med. Chem. Lett. 2022, 13: 105-110.

  10. Kazemi, S.; Kawaguchi, S.; Badr, C.E.; Mattos, D.R.; Ruiz-Saenz, A.; Serrill, J.D.; Moasser, M.M.; Dolan, B.P.; Paavilainen, V.O.; Oishi, S.; McPhail, K.L.; Ishmael, Jane E. Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A. Biochemical Pharmacology 2021, 183, 114317.

  11. Tranter, D., Paatero, A.O., Kawaguchi, S., Kazemi, S., Serrill, J.D.; Kellosalo, J., Vogel, W.K., Richter, U., Mattos, D.R., Wan, X., Thornburg, C.C.; Oishi, S., McPhail, K.L.; Ishmael, J.E., Paavilainen, V.O. Coibamide A targets Sec61 to prevent biogenesis of secretory and membrane proteins. ACS Chemical Biology, 2020, 15, 8, 2125–2136.

  12. Aron A.T.,* Gentry E.C.,* McPhail, K.L*…Dorrestein, P.D. et al. Reproducible molecular networking of untargeted mass spectrometry data using GNPS. Nat Protoc. 2020, 15(6):1954-1991. PubMed ID: 32405051.

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