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

Peter I. O’Daniel^†, Zhihong Peng^†, Hualiang Pi^†, Sebastian A. Testero^†, Derong Ding^†, Edward Spink^†, Erika Leemans^†, Marc A. Boudreau^†, Takao Yamaguchi^†, Valerie A. Schroeder^‡, William R. Wolter^‡, Leticia I. Llarrull^†, Wei Song^†, Elena Lastochkin^†, Malika Kumarasiri^†, Nuno T. Antunes^†, Mana Espahbodi^†, Katerina Lichtenwalter^†, Mark A. Suckow^‡, Sergei Vakulenko^†, Shahriar Mobashery*^†, and Mayland Chang*^†

^† Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States

^‡ Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, United States

J. Am. Chem. Soc., 2014, 136 (9), pp 3664–3672

DOI: 10.1021/ja500053x

Publication Date (Web): February 11, 2014

mobashery@nd.edu, mchang@nd.edu

ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

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-β-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycin- and linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100% oral bioavailability.

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Article

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

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

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