Approaches to the simultaneous inactivation of metallo- and serine-β-lactamases

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• 作者：Sudhakar Reddy Ganta ; Senthil Perumal ; Sundar Ram Reddy Pagadala ; &#xd8 ; rjan Samuelsen ; James Spencer ; R.F. Pratt ; John D. Buynak
• 关键词：β ; -Lactamase ; Antibiotic ; Penicillin ; Cephalosporin ; Hydroxamate ; Reverse hydroxamate
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：15 March 2009
• 年：2009
• 卷：19
• 期：6
• 页码：1618-1622
• 全文大小：316 K

文摘

A series of cephalosporin-derived reverse hydroxamates and oximes were prepared and evaluated as inhibitors of representative metallo- and serine-β-lactamases. The reverse hydroxamates showed submicromolar inhibition of the GIM-1 metallo-β-lactamase. With respect to interactions with the classes A, C, and D serine β-lactamases, as judged by their correspondingly low K_m values, the reverse hydroxamates were recognized in a manner similar to the non-hydroxylated N–H amide side chains of the natural substrates of these enzymes. This indicates that, with respect to recognition in the active site of the serine β-lactamases, the OC–NR–OH functionality can function as a structural isostere of the OC–NR–H group, with the N–O–H group presumably replacing the amide N–H group as a hydrogen bond donor to the appropriate backbone carbonyl oxygen of the protein. The reverse hydroxamates, however, displayed k_cat values up to three orders of magnitude lower than the natural substrates, thus indicating substantial slowing of the hydrolytic action of these serine β-lactamases. Although the degree of inactivation is not yet enough to be clinically useful, these initial results are promising. The substitution of the amide N–H bond by N–OH may represent a useful strategy for the inhibition of other serine hydrolases.