The Novel Oxazolidinone TBI-223 Is Effective in Three Preclinical Mouse Models of Methicillin-Resistant Staphylococcus aureus Infection.

Abstract

Staphylococcus aureus is an important cause of various infections in humans, including bacteremia, skin and soft tissue infections, and infections associated with implanted medical devices. The emergence of hospital- and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) underscores the urgent and unmet need to develop novel, safe, and effective antibiotics against these multidrug-resistant clinical isolates. Oxazolidinone antibiotics such as linezolid have excellent oral bioavailability and provide coverage against MRSA infections. However, their widespread and long-term use is often limited by adverse effects, especially myelosuppression. TBI-223 is a novel oxazolidinone with potentially reduced myelosuppression, compared to linezolid, but its efficacy against MRSA infections is unknown. Therefore, the preclinical efficacy of TBI-223 (80 and 160 mg/kg twice daily) was compared with that of linezolid (40 and 80 mg/kg twice daily) and sham treatment in mouse models of MRSA bacteremia, skin wound infection, and orthopedic-implant-associated infection. The dosage was selected based on mouse pharmacokinetic analysis of both linezolid and TBI-223, as well as measurement of the MICs. In all three models, TBI-223 and linezolid had comparable dose-dependent efficacies in reducing bacterial burden and disease severity, compared with sham-treated control mice. Taken together, these findings indicate that TBI-223 represents a novel oxazolidinone antibiotic that may provide an additional option against MRSA infections. Future studies in larger animal models and clinical trials are warranted to translate these findings to humans. IMPORTANCE Staphylococcus aureus is the predominant cause of bloodstream, skin, and bone infections in humans. Resistance to commonly used antibiotics is a growing concern, making it more difficult to treat staphylococcal infections. Use of the oxazolidinone antibiotic linezolid against resistant strains is hindered by high rates of adverse reactions during prolonged therapy. Here, a new oxazolidinone named TBI-223 was tested against S. aureus in three mouse models of infection, i.e., bloodstream infection, skin infection, and bone infection. We found that TBI-223 was as effective as linezolid in these three models. Previous data suggest that TBI-223 has a better safety profile than linezolid. Taken together, these findings indicate that this new agent may provide an additional option against MRSA infections. Future studies in larger animal models and clinical trials are warranted to translate these findings to humans.

• Authors: Oren Gordon, Dustin A Dikeman, Roger V Ortines, Yu Wang, Christine Youn, Mohammed Mumtaz, Nicholas Orlando, Jeffrey Zhang, Aman M Patel, Ethan Gough, Amit Kaushik, Eric L Nuermberger, Anna M Upton, Nader Fotouhi, Lloyd S Miller, Nathan K Archer
• Journal: Microbiology spectrum (Microbiol Spectr) Vol. 10 Issue 5 Pg. e0245121 (10 26 2022) ISSN: 2165-0497 [Electronic] United States
• PMID: 36106881 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Anti-Bacterial Agents
• Linezolid
• Oxazolidinones

Topics

• Animals
• Mice
• Acetamides (pharmacology, therapeutic use)
• Anti-Bacterial Agents (adverse effects)
• Bacteremia (drug therapy)
• Linezolid (adverse effects)
• Methicillin-Resistant Staphylococcus aureus
• Microbial Sensitivity Tests
• Oxazolidinones (adverse effects)
• Staphylococcal Infections (drug therapy, microbiology)
• Staphylococcus aureus