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

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 methicillin-resistant 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 membrane-active 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.

• Authors: 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 Vlahovska, William M Wuest, Huajian Gao, Frederick M Ausubel, Eleftherios Mylonakis
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 33 Pg. 16529-16534 (08 13 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31358625 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Gentamicins
• Lipid Bilayers
• Phosphatidylcholines
• Unilamellar Liposomes
• Cholesterol
• Bithionol
• 1-palmitoyl-2-oleoylphosphatidylcholine

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Bithionol (pharmacology)
• Cell Membrane (drug effects)
• Cell Membrane Permeability (drug effects)
• Cholesterol (chemistry)
• Disease Models, Animal
• Drug Repositioning
• Drug Synergism
• Gentamicins (pharmacology)
• Lipid Bilayers (chemistry)
• Membrane Fluidity (drug effects)
• Methicillin-Resistant Staphylococcus aureus (drug effects, ultrastructure)
• Molecular Dynamics Simulation
• Phosphatidylcholines (chemistry)
• Structure-Activity Relationship
• Unilamellar Liposomes