TY - JOUR
T1 - The Novel Oxazolidinone TBI-223 Is Effective in Three Preclinical Mouse Models of Methicillin-Resistant Staphylococcus aureus Infection
AU - Gordon, Oren
AU - Dikeman, Dustin A.
AU - Ortines, Roger V.
AU - Wang, Yu
AU - Youn, Christine
AU - Mumtaz, Mohammed
AU - Orlando, Nicholas
AU - Zhang, Jeffrey
AU - Patel, Aman M.
AU - Gough, Ethan
AU - Kaushik, Amit
AU - Nuermberger, Eric L.
AU - Upton, Anna M.
AU - Fotouhi, Nader
AU - Miller, Lloyd S.
AU - Archer, Nathan K.
N1 - Publisher Copyright:
© 2022 Gordon et al.
PY - 2022/9
Y1 - 2022/9
N2 - 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 communityacquired 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.
AB - 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 communityacquired 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.
KW - Staphylococcus aureus
KW - antibiotic resistance
KW - oxazolidinones
UR - http://www.scopus.com/inward/record.url?scp=85140856714&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85140856714&partnerID=8YFLogxK
U2 - 10.1128/spectrum.02451-21
DO - 10.1128/spectrum.02451-21
M3 - Article
C2 - 36106881
AN - SCOPUS:85140856714
SN - 2165-0497
VL - 10
JO - Microbiology Spectrum
JF - Microbiology Spectrum
IS - 5
ER -