期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 3, 页码 1084-1097出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm301490d
关键词
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资金
- Case Western Reserve University [T32 GM07250]
- Veterans Affairs Career Development Program
- Veterans Affairs Merit Review Program
- VISN [10 GRECC]
- NIH [1R01-A1063517, 1R01-A100560]
Inhibitor resistant (IR) class A beta-lactamases pose a significant threat to many current antibiotic combinations. The K234R substitution in the SHV beta-lactamase, from Klebsiella pneumoniae, results in resistance to ampicillin/clavulanate. After site-saturation mutagenesis of Lys-234 in SHV, microbiological and biochemical characterization of the resulting beta-lactamases revealed that only -Arg conferred resistance to ampicillin/clavulanate. X-ray crystallography revealed two conformations of Arg-234 and Ser-130 in SHV K234R. The movement of Ser-130 is the principal cause of the observed clavulanate resistance. A panel of boronic acid inhibitors was designed and tested against SHV-1 and SHV K234R. A chiral ampicillin analogue was discovered to have a 2.4 +/- 0.2 nM K-i for SHV K234R; the chiral ampicillin analogue formed a more complex hydrogen-bonding network in SHV K234R vs SHV-1. Consideration of the spatial position of Ser-130 and Lys-234 and this hydrogen-bonding network will be important in the design of novel antibiotics targeting IR beta-lactamases.
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