Inhibitor resistant (IR) class A β -lactamases pose a signi fi cant 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 character- ization 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 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 β -lactamases.

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; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Focco van den, Akker; Robert A., Bonomo. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:(2013), pp. 1084-1097. [10.1021/jm301490d]

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

ROMAGNOLI, Chiara;CASELLI, Emilia;PRATI, Fabio;
2013

Abstract

Inhibitor resistant (IR) class A β -lactamases pose a signi fi cant 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 character- ization 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 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 β -lactamases.
2013
56
1084
1097
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; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Focco van den, Akker; Robert A., Bonomo. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:(2013), pp. 1084-1097. [10.1021/jm301490d]
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; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Focco van den, Akker; Robert A., Bonomo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/921689
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