Repurposing Eltrombopag for Multidrug Resistant Staphylococcus aureus Infections

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Antimicrobial resistance (AMR) poses a significant threat to global health, necessitating novel therapeutic strategies.
• Drug repurposing offers an accelerated pathway to discover and develop new antibiotics by screening existing, approved medications.

Purpose of the Study:

• To identify FDA-approved drugs with potential antibacterial activity against Staphylococcus aureus.
• To evaluate the efficacy of identified drug candidates, particularly eltrombopag, against various S. aureus strains and in preclinical models.

Main Methods:

• Screening of 182 FDA-approved drugs for activity against S. aureus.
• Determination of Minimum Inhibitory Concentration (MIC50) for active compounds against sensitive and resistant strains.
• Assessment of eltrombopag's efficacy in a cell infection model and a mouse infection model.

Main Results:

• Three FDA-approved drugs, including LDK378 (Ceritinib), dronedarone HCl, and eltrombopag, exhibited antibacterial activity against S. aureus.
• Eltrombopag demonstrated potent activity against a wide range of clinical isolates, including methicillin-resistant S. aureus (MRSA), with MIC50 values between 1.4-3.2 mg/L.
• Eltrombopag effectively inhibited bacterial growth in vitro and reduced bacterial loads in vivo in a mouse model of infection.

Conclusions:

• Eltrombopag is a promising repurposed drug candidate with significant potential as a novel antibiotic against S. aureus, including resistant strains.
• The study highlights the value of drug repurposing in the fight against antimicrobial resistance.
• Further investigation into eltrombopag's mechanism of action and clinical efficacy is warranted.