A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus
| Autor: | Gabriel L. Hendricks, Kiho Lee, Xiaowen Huang, Taylor P. A. Hari, Jenna Port, Frederick M. Ausubel, Madeline M Dekarske, Noelly Queiroz Ribeiro, Hammad A. Faizi, Jake L Rosen, Andrew D. Steele, Wen Pan, Beth Burgwyn Fuchs, Guijin Zou, William M. Wuest, Eleftherios Mylonakis, Wenpeng Zhu, Nicolas Galle, Erika E Csatary, Petia M. Vlahovska, Huajian Gao, Ingrid K. Wilt, Katerina Tori, Wooseong Kim |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Multidisciplinary Multidrug tolerance medicine.drug_class 030106 microbiology Antibiotics medicine.disease_cause Antimicrobial Methicillin-resistant Staphylococcus aureus Microbiology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Bithionol chemistry medicine Membrane fluidity Gentamicin Lipid bilayer medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 116:16529-16534 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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