In Vitro and In Vivo Synergy of the Oxadiazole Class of Antibacterials with β-Lactams

Author:

Janardhanan Jeshina1,Meisel Jayda E.1,Ding Derong1,Schroeder Valerie A.2,Wolter William R.2,Mobashery Shahriar1,Chang Mayland1

Affiliation:

1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

2. Freimann Life Science Center and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA

Abstract

ABSTRACT The oxadiazole antibacterials target the bacterial cell wall and are bactericidal. We investigated the synergism of ND-421 with the commonly used β-lactams and non-β-lactam antibiotics by the checkerboard method and by time-kill assays. ND-421 synergizes well with β-lactam antibiotics, and it also exhibits a long postantibiotic effect (4.7 h). We also evaluated the in vivo efficacy of ND-421 in a murine neutropenic thigh infection model alone and in combination with oxacillin. ND-421 has in vivo efficacy by itself in a clinically relevant infection model (1.49 log 10 bacterial reduction for ND-321 versus 0.36 log 10 for linezolid with NRS119) and acts synergistically with β-lactam antibiotics in vitro and in vivo , and the combination of ND-421 with oxacillin is efficacious in a mouse neutropenic thigh methicillin-resistant Staphylococcus aureus (MRSA) infection model (1.60 log 10 bacterial reduction). The activity of oxacillin was potentiated in the presence of ND-421, as the strain would have been resistant to oxacillin otherwise.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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