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

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.