Repurposed membrane-targeting RS17053 eradicates MRSA persisters and enhances aminoglycoside killing

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat due to antibiotic-tolerant persister cells.
• These dormant MRSA persisters evade conventional antimicrobial therapies, leading to persistent infections.

Purpose of the Study:

• To investigate RS17053, a selective α1A-adrenoceptor antagonist, as a potential therapeutic agent against MRSA.
• To characterize the mechanism of action and efficacy of RS17053 against antibiotic-resistant and tolerant S. aureus.

Main Methods:

• RS17053 was tested for its activity against S. aureus, including persister cells.
• Its effects on bacterial membrane integrity, intracellular contents, and reactive oxygen species were analyzed.
• Synergistic effects with aminoglycosides and in vivo efficacy in a Caenorhabditis elegans model were evaluated.

Main Results:

• RS17053 demonstrated potent activity against both antibiotic-resistant and tolerant S. aureus by disrupting bacterial phospholipid bilayers.
• The compound induced membrane permeabilization, intracellular leakage, and cell death with minimal mammalian cell toxicity.
• RS17053 showed no resistance development, enhanced aminoglycoside efficacy, and protected hosts in a C. elegans infection model.

Conclusions:

• RS17053 is a membrane-active compound with significant antimicrobial potential against persistent MRSA.
• It can be repurposed as a direct-acting agent or an adjuvant therapy to potentiate aminoglycosides for treating MRSA infections.