title: Discovery of a new class of non-β-lactam inhibitors of penicillin-binding proteins with Gram-positive antibacterial activity.
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.
authors: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors: Peter I
authors: PI
authors: O'Daniel
authors: Zhihong
authors: Z
authors: Peng
authors: Hualiang
authors: H
authors: Pi
authors: Sebastian A
authors: SA
authors: Testero
authors: Derong
authors: D
authors: Ding
authors: Edward
authors: E
authors: Spink
authors: Erika
authors: E
authors: Leemans
authors: Marc A
authors: MA
authors: Boudreau
authors: Takao
authors: T
authors: Yamaguchi
authors: Valerie A
authors: VA
authors: Schroeder
authors: William R
authors: WR
authors: Wolter
authors: Leticia I
authors: LI
authors: Llarrull
authors: Wei
authors: W
authors: Song
authors: Elena
authors: E
authors: Lastochkin
authors: Malika
authors: M
authors: Kumarasiri
authors: Nuno T
authors: NT
authors: Antunes
authors: Mana
authors: M
authors: Espahbodi
authors: Katerina
authors: K
authors: Lichtenwalter
authors: Mark A
authors: MA
authors: Suckow
authors: Sergei
authors: S
authors: Vakulenko
authors: Shahriar
authors: S
authors: Mobashery
authors: Mayland
authors: M
authors: Chang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002473:Cell Wall / Q000187:drug effects; D003198:Computer Simulation; D055808:Drug Discovery; D006094:Gram-Positive Bacteria / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010069:Oxadiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D047090:beta-Lactams / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D010069:Oxadiazoles; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams