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

SR Ganta, S Perumal, SR Pagadala, O Samuelsen, J Spencer, RF Pratt, JD Buynak

Research output: Contribution to journalArticle (Academic Journal)peer-review

23 Citations (Scopus)

Abstract

A series of cephalosporin-derived reverse hydroxamates and oximes were prepared and evaluated as inhibitors of representative metallo- and serine-beta-lactamases. The reverse hydroxamates showed submicromolar inhibition of the GIM-1 metallo-beta-lactamase. With respect to interactions with the classes A, C, and D serine beta-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 beta-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 beta-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.
Translated title of the contributionApproaches to the simultaneous inactivation of metallo- and serine-beta-lactamases
Original languageEnglish
Pages (from-to)1618 - 1622
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume19
DOIs
Publication statusPublished - Feb 2009

Fingerprint Dive into the research topics of 'Approaches to the simultaneous inactivation of metallo- and serine-beta-lactamases'. Together they form a unique fingerprint.

Cite this