Discovery of a New Class of Non-beta-lactam Inhibitors of Penicillin- Binding Proteins with Gram-Positive Antibacterial Activity

O'DANIEL, P.I.; PENG, Z.; PI, H.; TESTERO, S.A.; DING, D.; SPINK, E.; LEEMANS, E.; BOUDREAU, M.A.; YAMAGUCHI, T.; SCHROEDER, V.A.; WOLTER, W.R.; LLARRULL, L.I.; SONG, W.; LASTOCHKIN, E.; KUMARASIRI, M.; ANTUNES, N.T.; ESPAHBODI, M.; LICHTENWALTER, K.; SUCKOW, M.A.; VAKULENKO, S.; MOBASHERY, S.; CHANG, M.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

AMER CHEMICAL SOC

Lugar: Washington; Año: 2014 vol. 136 p. 3664 - 3672

0002-7863

Infections caused by hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA) are a serious global public-health concern, as MRSA has become broadly resistant to many classes of antibiotics. We disclose herein the discovery of a new class of non-beta-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycinand linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100% oral bioavailability.