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Updated: Jan 21, 2026
Subcutaneous Infection of Methicillin Resistant Staphylococcus Aureus MRSA
Published on: February 9, 2011
A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant
Wooseong Kim1, Guijin Zou2, Taylor P A Hari3
1Division of Infectious Diseases, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903.
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.
Insights
The repurposed drug bithionol effectively eliminates antibiotic-tolerant Staphylococcus aureus (persister cells) by disrupting bacterial membranes. This discovery offers a new strategy against persistent infections, including methicillin-resistant Staphylococcus aureus (MRSA).
Area of Science:
- Microbiology and Infectious Diseases
- Biophysics
- Pharmacology
Background:
- Antibiotic tolerance in Staphylococcus aureus, particularly methicillin-resistant Staphylococcus aureus (MRSA), poses a significant clinical challenge.
- Persister cells, a dormant, nongrowing subpopulation of bacteria, contribute to treatment failure and chronic infections.
- Novel therapeutic strategies are needed to effectively eradicate these antibiotic-tolerant bacterial populations.
Purpose of the Study:
- To investigate the potential of the anthelmintic agent bithionol in eliminating MRSA persister cells.
- To elucidate the mechanism of action of bithionol against bacterial membranes.
- To establish a biophysical indicator for predicting the efficacy of membrane-active agents against persisters.
Main Methods:
- Treatment of MRSA persister cells with bithionol.
- All-atom molecular dynamics (MD) simulations to assess bithionol's interaction with bacterial and mammalian lipid bilayers.
- Measurement of membrane fluidity and permeabilization.
- In vivo efficacy studies in a mouse model of chronic MRSA infection using bithionol in combination with gentamicin.
Main Results:
- Bithionol effectively kills MRSA persister cells by disrupting the integrity of bacterial membranes.
- Bithionol exhibits significant selectivity for bacterial over mammalian cell membranes, confirmed by MD simulations.
- Increased membrane fluidity correlates with the antipersister potency of membrane-active compounds like bithionol.
- Combination therapy with bithionol and gentamicin significantly reduced bacterial burdens in a mouse infection model.
Conclusions:
- Bithionol demonstrates significant potential as a repurposed therapeutic agent against antibiotic-tolerant MRSA infections.
- Disruption of bacterial membrane integrity and increased membrane fluidity are key mechanisms for antipersister activity.
- Membrane fluidity serves as a reliable biophysical indicator for predicting the efficacy of novel antipersister agents.
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