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Small Molecules Disrupting Bacterial Cell Membranes

Antibiotic resistance continues to be an increasingly important issue to combat as bacteria develop new mechanisms of resistance and current antibiotics become less effective. We have synthesized/studied small molecules and related analogs, some of which have been made in collaboration with the Mylonakis lab group at Brown University. These molecules have been shown to kill bacteria through disruption of bacterial membranes, specifically in methicillin-resistant Staphylococcus aureus (MRSA). Investigation is ongoing regarding the mechanisms of action of these molecules and their interactions with bacterial membranes.

Cheng, A.V.; Kim, W.; Escobar, I.E.; Mylonakis, E.; Wuest, W.M.* “Structure-Activity Relationship and Anticancer Profile of Second-Generation Anti-MRSA Synthetic Retinoids” ACS Med. Chem. Lett. 2020 ASAP DOI: 10.1021/acsmedchemlett.9b00159 (Featured in the Women of Medicinal Chemistry Issue)

Kim, W.; Zou, G.; Hari, T.P.A.; Wilt, I.K.; Zhu, W.; Galle, N.; Faizi, H.A.; Hendricks, G.L.; Tori. K.; Pan, W.; Huang, X.; Steele, A.D.; Csatary, E.E.; Dekarske, M.M.; Rosen, J.L.; de Queiroz Ribiero, N.; Lee, K.; Port, J.; Fuchs, B.B.; Vlahovska, P.M.; Wuest, W.M.; Gao, H.; Ausubel, F.M.; Mylonakis,E. “A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus” Proc. Nat. Acad. Sci. 2019 116, 16529 DOI: 10.1073/pnas.1904700116 (Featured on NPR)

Kim, W.; Steele, A.D.; Zhu, W.; Csatary, E.E.; Fricke, N.; Dekarske, M.M.; Jayamani, E.; Pan, W.; Kwon, B.; Sinitsa, I.F.; Rosen, J.; Conery, A.L.; Fuchs, B.B.; Vlahovska, P.M.; Ausubel, F.M.; Gao, H.; Wuest, W.M.*; Mylonakis, E. “Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters” ACS Infectious Diseases 2018 4, 1540 DOI: 10.1021/acsinfecdis.8b00161

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.; Rajamuthiah, R.; Fuchs, B.B.; Vlahovska, P.M.; Wuest, W.M.; Gilmore, M.S.; Gao, H.; Ausubel, F.M.; Mylonakis, E. “A new class of synthetic retinoid antibiotics effective against bacterial persisters” Nature 2018 556, 103.  DOI: 10.1038/nature26157