Design and Exploration of Novel Boronic Acid Inhibitors Reveals Important Interactions with a Clavulanic Acid-Resistant Sulfhydryl-Variable (SHV) 尾-Lactamase
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- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：February 14, 2013
- 年：2013
- 卷：56
- 期：3
- 页码：1084-1097
- 全文大小：586K
- 年卷期：v.56,no.3(February 14, 2013)
- ISSN：1520-4804
文摘
Inhibitor resistant (IR) class A 尾-lactamases pose a significant threat to many current antibiotic combinations. The K234R substitution in the SHV 尾-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 尾-lactamases revealed that only 鈭扐rg 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 卤 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 尾-lactamases.