Design and exploration of novel boronic acid inhibitors reveals important interactions with a clavulanic acid-resistant sulfhydryl-variable (SHV) β-lactamase

Marisa L. Winkler, Elizabeth A. Rodkey, Magdalena A. Taracila, Sarah M. Drawz, Christopher R. Bethel, Krisztina M. Papp-Wallace, Kerri M. Smith, Yan Xu, Jeffrey R. Dwulit-Smith, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Focco Van Den Akker, Robert A. Bonomo

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1084-1097
Number of pages14
JournalJournal of medicinal chemistry
Volume56
Issue number3
DOIs
StatePublished - Feb 14 2013

Fingerprint Dive into the research topics of 'Design and exploration of novel boronic acid inhibitors reveals important interactions with a clavulanic acid-resistant sulfhydryl-variable (SHV) β-lactamase'. Together they form a unique fingerprint.

Cite this