TY - JOUR
T1 - Structure-activity relationship for the oxadiazole class of antibiotics
AU - Spink, Edward
AU - Ding, Derong
AU - Peng, Zhihong
AU - Boudreau, Marc A.
AU - Leemans, Erika
AU - Lastochkin, Elena
AU - Song, Wei
AU - Lichtenwalter, Katerina
AU - O'Daniel, Peter I.
AU - Testero, Sebastian A.
AU - Pi, Hualiang
AU - Schroeder, Valerie A.
AU - Wolter, William R.
AU - Antunes, Nuno T.
AU - Suckow, Mark A.
AU - Vakulenko, Sergei
AU - Chang, Mayland
AU - Mobashery, Shahriar
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/2/12
Y1 - 2015/2/12
N2 - 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.
AB - 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.
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U2 - 10.1021/jm501661f
DO - 10.1021/jm501661f
M3 - Article
C2 - 25590813
AN - SCOPUS:84922819956
SN - 0022-2623
VL - 58
SP - 1380
EP - 1389
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -