Chemical Biology

In addition to chemical synthesis, we desire to understand how our molecules exert their antimicrobial activity. We do this through in-house biological assays and collaborations with experts in the field. For example, promysalin’s mechanism of action and molecular target was probed with many different assays such as metal binding, resistance selection, and proteomics. In addition, our lab has expertise with molecules that perturb bacterial membranes and has used various fluorometric and absorbance-based probes to understand how these molecules work. We can also study how bacteria respond to a molecule by imaging and quantifying biofilm along with other virulence factors. Together, these tools give us a deeper understanding of our molecules and help advance our knowledge of bacteria’s response to antimicrobial compounds.

Publications
1. Scharnow, A. M.; Solinski, A. E.; Rowe, S.; Drechsel, I.; Zhang,H.; Shaw, E.; Page, J. E.; Wu, H.; Sieber, S. A.; Wuest, W. M. ”In SituBiofilm Affinity-Based Protein Profiling Identifies the StreptococcalHydrolase GbpB as the Target of a Carolacton-Inspired ChemicalProbe.” J. Am. Chem. Soc. 2024, 146, 23449
2. Sommers, K. J.; Marina E. M.; Cody E. H.; Amber M. S.; Lauren E. A; Ashley A. P.; Robert G. C.; Kevin PC M.; and William M. W. “Quaternary phosphonium compounds: an examination of non-nitrogenous cationic amphiphiles that evade disinfectant resistance.” ACS Infect. Dis., 2022, 8, 387
3. Hübner, I.; Shapiro, J. A.; Hoßmann, J.; Drechsel, J.; Hacker, S. M.; Rather, P.N.; Pieper, D. H.; Wuest, W. M. and Sieber, S. A. ”Broad spectrum antibiotic xanthocillin X effectively kills Acinetobacter baumannii via dysregulation of heme biosynthesis.” ACS Central Science, 2021, 7, 488.
4. Le, P.; Kunold, E.; Macsics, R.; Rox, K.; Jennings, M.C.; Ugur, I.; Reinecke, M.; Chaves-Moreno, D.; Hackl, M.W.; Fetzer, C.; Mandl, F. A.; Lehmann, J; Korotkov, V. S.; Hacker, S. M.; Kuster, B.; Antes, I.; Pieper, D. H.; Rohde, M.; Wuest, W. M.; Medina, E.; Sieber, S. A. 2020. ”Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms.” Nature chemistry, 2020, 12, 145-158.
5. Kim, W.; Zou, G.; Hari, T.P.; Wilt, I.K.; Zhu, W.; Galle, N.; Faizi, H.A.; Hendricks, G.L.; Tori, K.; Pan, W.; Huang, X. ”A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus.” Proc. Nat. Acad. Sci. 2019, 116, 16529.
6. Keohane, C.E.; Steele, A.D.; Fetzer, C.; Khowsathit, J.; Van Tyne, D.; Moynie, L.; Gilmore, M.S.; Karanicolas, J.; Sieber, S.A.; Wuest, W.M.* “Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase” J. Am. Chem. Soc. 2018 140, 1774