1421842-15-0Relevant articles and documents
Design and exploration of novel boronic acid inhibitors reveals important interactions with a clavulanic acid-resistant sulfhydryl-variable (SHV) β-lactamase
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,Bonomo, Robert A.
, p. 1084 - 1097 (2013)
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.
