Design and Exploration of Novel Boronic Acid Inhibitors Reveals Important Interactions with A Clavulanic Acid-Resistant Sulfhydryl-Variable (SHV) β-Lactamase
Document Type
Article
Publication Date
2-14-2013
Publication Title
Journal of Medicinal Chemistry
Abstract
Inhibitor resistant (IR) class A β-lactamases pose a significant threat to many current antibiotic combinations. The K234R substitution in the SHV β-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 β-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 Ki 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 β-lactamases.
Recommended Citation
Winkler, Marisa L.; Rodkey, Elizabeth A.; Taracila, Magdalena A.; Drawz, Sarah M.; Bethel, Christopher R.; Papp-Wallace, Krisztina M.; Smith, Kerri M.; Xu, Yan; Dwulit-Smith, Jeffrey R.; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; van den Akker, Focco; and Bonomo, Robert A., "Design and Exploration of Novel Boronic Acid Inhibitors Reveals Important Interactions with A Clavulanic Acid-Resistant Sulfhydryl-Variable (SHV) β-Lactamase" (2013). Chemistry Faculty Publications. 242.
https://engagedscholarship.csuohio.edu/scichem_facpub/242
DOI
10.1021/jm301490d
Volume
56
Issue
3
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Comments
M.L.W. has been supported by Medical Scientist Training Program Training Grant, Case Western Reserve University-T32 GM07250. K.P.W. is funded by the Veterans Affairs Career Development Program. R.A.B. is funded by Veterans Affairs Merit Review Program, VISN 10 GRECC, and NIH grants 1R01-A1063517 and 1R01-A100560.