Medicinal Chemistry

The Wuest Lab engages in a number of collaborative projects with groups specializing in a wide range of expertise. Our medicinal chemistry endeavors aim to repurpose old drugs for novel targets and/or identify new compounds that use unique binding modes to inhibit already-validated targets. Alongside the Conn Lab, we used computational techniques to identify berberine conjugates targeting the MexXY-OprM efflux pump. With the Mylokanis group, we uncovered the antimicrobial effects and safety profiles of synthetic retinoid analogs. Additionally, we have performed extensive structure-activity relationship (SAR) studies for antibiotic compounds targeting succinate dehydrogenase (Sdh) and a protease repressor, LexA. Ongoing projects exploit the ever-expanding toolbox of chemical transformation methodologies to access and edit antimicrobial small molecules in a divergent manner.

Publications

1. Toles, Z. E.; Thierer, L. M.; Wu, A.; Bezold, E. L.; Rachii, D.; Sanchez, C. A.; Vargas‐Cuebas, G. G.; Keller, T. M.; Carroll, P. J.; Wuest, W. M.; Minbiole, K.P. 2024. ”Bushy‐Tailed QACs: The Development of Multicationic Quaternary Ammonium Compounds with a High Degree of Alkyl Chain Substitution.” ChemMedChem, 2024, 19, e202400301.

2. Mahoney, A. R.; Storek, K. M.; Wuest, W. M. ”Structure-BasedDesign of Promysalin Analogues to Overcome Mechanisms of Bacterial Resistance” ACS Omega 2023, 8, 12558

3. Cheng, A.V.C.^#; Cory, M.B.^#; Li, A.; Kohli, R.M.*; Wuest, W.M.* “Exploration of inhibitors of the bacterial LexA repressor-protease” Bioorg. Med. Chem. Lett. 2022 65, 128702

4. Post, S.J.^#; Keohane, C.E.^#; Rossiter, L.M.; Kaplan, A.R.; Khowsathit, J.; Matuska, K.; Karanicolas, J.; Wuest, W.M.* “Target-based design of promysalin analogs identifies a new putative binding cleft in succinate dehydrogenase” ACS Infectious Diseases 2020 6, 1372

5. Korobeynikov, V.; Borakove, M.; Feng, Y.; Wuest, W. M.; Koval, A. B.; Nikonova, A. S.; Serebriiskii, I., Chernoff, J., Borges, V. F.; Golemis, E. A.; Shagisultanova, E. ”Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer.” Breast Cancer Research & Treatment 2019 117, 369.

6. Kim, W.; Zhu, W.; Hendricks, G. L.; Van Tyne, D.; Steele, A. D.; Keohane, C. E.; Fricke, N.; Conery, A. L.; Shen, S.; Pan, W.; Lee, K. ”A new class of synthetic retinoid antibiotics effective against bacterial persisters.” Nature, 2018, 556,103.