Abstract
The continuous rise of antimicrobial resistance urgently demands new therapeutic agents for human health. Drug repurposing is an attractive strategy that could significantly save time delivering new antibiotics to clinics. We screened 182 US Food and Drug Administration (FDA)-approved drugs to identify potential antibiotic candidates against Staphylococcus aureus, a major pathogenic bacterium. This screening revealed the significant antibacterial activity of three small molecule drugs against S. aureus: (1) LDK378 (Ceritinib), an anaplastic lymphoma kinase (ALK) inhibitor for the treatment of lung cancer, (2) dronedarone HCl, an antiarrhythmic drug for the treatment of atrial fibrillation, and (3) eltrombopag, a thrombopoietin receptor agonist for the treatment of thrombocytopenia. Among these, eltrombopag showed the highest potency against not only a drug-sensitive S. aureus strain but also 55 clinical isolates including 35 methicillin-resistant S. aureus (Minimum inhibitory concentration, MIC, to inhibit 50% growth [MIC50] = 1.4–3.2 mg/L). Furthermore, we showed that eltrombopag inhibited bacterial growth in a cell infection model and reduced bacterial loads in infected mice, demonstrating its potential as a new antibiotic agent against S. aureus that can overcome current antibiotic resistance.
Highlights
But showed no activity against the three Gram-negative bacteria (Supplementary Table S2). These results suggested that eltrombopag likely has the activity against Gram-positive bacteria but not Gram-negative bacteria, which might cause less collateral damages and resistance in the resident microbiota compared to broad spectrum antibiotics [10]
We found that S. aureus growth decreased by eltrombopag in both conditions with (MIC50 = 1.2 ± 0.6 mg/L) and without (MIC50 = 1.5 ± 0.2 mg/L) gentamicin treatment similar to vancomycin (Figure 3A,B)
Among 12 drugs identified with potential antibacterial activity, eltrombopag, a drug approved for thrombocytopenia, showed the most significant antibacterial activity against multidrug-resistant S. aureus
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Antibiotic resistance is one of the greatest threats to global public health, which could cause the pandemic. Development of effective therapeutic agents is vital to prepare for a battle against antibiotic resistant infections. S. aureus is a leading cause of bacterial infections worldwide and remains a major public health concern due to the emergence and rapid spread of drug-resistant strains, such as methicillin-resistant S. aureus (MRSA). The vancomycin-resistant strain that was reported in the United States in 2002 [1].
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