A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus

Wooseong Kim, Guijin Zou, Taylor P.A. Hari, Ingrid K. Wilt, Wenpeng Zhu, Nicolas Galle, Hammad A. Faizi, Gabriel L. Hendricks, Katerina Tori, Wen Pan, Xiaowen Huang, Andrew D. Steele, Erika E. Csatary, Madeline M. Dekarske, Jake L. Rosen, Noelly De Queiroz Ribeiro, Kiho Lee, Jenna Port, Beth Burgwyn Fuchs, Petia M. VlahovskaWilliam M. Wuest, Huajian Gao, Frederick M. Ausubel*, Eleftherios Mylonakis

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillinresistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membraneactive antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.

Original languageEnglish (US)
Pages (from-to)16529-16534
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number33
DOIs
StatePublished - 2019

Keywords

  • Bacterial persister
  • Drug repurposing
  • MRSA
  • Membrane selectivity
  • Membrane-active antimicrobials

ASJC Scopus subject areas

  • General

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    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 Ribeiro, N., Lee, K., Port, J., Fuchs, B. B., ... Mylonakis, E. (2019). A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus. Proceedings of the National Academy of Sciences of the United States of America, 116(33), 16529-16534. https://doi.org/10.1073/pnas.1904700116