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

ABSTRACT: Inhibitor resistant (IR) class A ?-lactamases pose a significant threat to many current antibiotic combinations. The K234R substitution in the SHV ?-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 ?-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 ?-lactamases.

SUBMITTER: Winkler ML

PROVIDER: S-EPMC3943433 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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

Winkler Marisa L ML Rodkey Elizabeth A EA Taracila Magdalena A MA Drawz Sarah M SM Bethel Christopher R CR Papp-Wallace Krisztina M KM Smith Kerri M KM Xu Yan Y Dwulit-Smith Jeffrey R JR Romagnoli Chiara C Caselli Emilia E Prati Fabio F van den Akker Focco F Bonomo Robert A RA

Journal of medicinal chemistry 20130204 3

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-2 ...[more]

PMID: 23252553

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Project description:BACKGROUND: SHV ?-lactamases confer resistance to a broad range of antibiotics by accumulating mutations. The number of SHV variants is steadily increasing. 117 SHV variants have been assigned in the SHV mutation table (http://www.lahey.org/Studies/). Besides, information about SHV ?-lactamases can be found in the rapidly growing NCBI protein database. The SHV ?-Lactamase Engineering Database (SHVED) has been developed to collect the SHV ?-lactamase sequences from the NCBI protein database and the SHV mutation table. It serves as a tool for the detection and reconciliation of inconsistencies, and for the identification of new SHV variants and amino acid substitutions. DESCRIPTION: The SHVED contains 200 protein entries with distinct sequences and 20 crystal structures. 83 protein sequences are included in the both the SHV mutation table and the NCBI protein database, while 35 and 82 protein sequences are only in the SHV mutation table and the NCBI protein database, respectively. Of these 82 sequences, 41 originate from microbial sources, and 22 of them are full-length sequences that harbour a mutation profile which has not been classified yet in the SHV mutation table. 27 protein entries from the NCBI protein database were found to have an inconsistency in SHV name identification. These inconsistencies were reconciled using information from the SHV mutation table and stored in the SHVED.The SHVED is accessible at http://www.LacED.uni-stuttgart.de/classA/SHVED/. It provides sequences, structures, and a multisequence alignment of SHV ?-lactamases with the corrected annotation. Amino acid substitutions at each position are also provided. The SHVED is updated monthly and supplies all data for download. CONCLUSIONS: The SHV ?-Lactamase Engineering Database (SHVED) contains information about SHV variants with reconciled annotation. It serves as a tool for detection of inconsistencies in the NCBI protein database, helps to identify new mutations resulting in new SHV variants, and thus supports the investigation of sequence-function relationships of SHV ?-lactamases.

Dataset Information

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

Publications

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

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