title: Structure-activity relationship for the oxadiazole class of antibiotics.
abstract: The structure-activity relationship (SAR) for the newly discovered oxadiazole class of antibiotics is described with evaluation of 120 derivatives of the lead structure. This class of antibiotics was discovered by in silico docking and scoring against the crystal structure of a penicillin-binding protein. They impair cell-wall biosynthesis and exhibit activities against the Gram-positive bacterium Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant and linezolid-resistant S. aureus. 5-(1H-Indol-5-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazole (antibiotic 75b) was efficacious in a mouse model of MRSA infection, exhibiting a long half-life, a high volume of distribution, and low clearance. This antibiotic is bactericidal and is orally bioavailable in mice. This class of antibiotics holds great promise in recourse against infections by MRSA.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Spink
authors.forename: Derong
authors.initials: D
authors.lastname: Ding
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Peng
authors.forename: Marc A
authors.initials: MA
authors.lastname: Boudreau
authors.forename: Erika
authors.initials: E
authors.lastname: Leemans
authors.forename: Elena
authors.initials: E
authors.lastname: Lastochkin
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Katerina
authors.initials: K
authors.lastname: Lichtenwalter
authors.forename: Peter I
authors.initials: PI
authors.lastname: O'Daniel
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Testero
authors.forename: Hualiang
authors.initials: H
authors.lastname: Pi
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.forename: Nuno T
authors.initials: NT
authors.lastname: Antunes
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Sergei
authors.initials: S
authors.lastname: Vakulenko
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D010069:Oxadiazoles