Using steric hindrance to design new inhibitors of class C β-lactamases

Indi Trehan, Federica Morandi, Larry C. Blaszczak, Brian K. Shoichet

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


β-lactamases confer resistance to β-lactam antibiotics such as penicillins and cephalosporins. However, β-lactams that form an acyl-intermediate with the enzyme but subsequently are hindered from forming a catalytically competent conformation seem to be inhibitors of β-lactamases. This inhibition may be imparted by specific groups on the ubiquitous R1 side chain of β-lactams, such as the 2-amino-4-thiazolyl methoxyimino (ATMO) group common among third-generation cephalosporins. Using steric hindrance of deacylation as a design guide, penicillin and carbacephem substrates were converted into effective β-lactamase inhibitors and antiresistance antibiotics. To investigate the structural bases of inhibition, the crystal structures of the acyl-adducts of the penicillin substrate amoxicillin and the new analogous inhibitor ATMO-penicillin were determined. ATMO-penicillin binds in a catalytically incompetent conformation resembling that adopted by third-generation cephalosporins, demonstrating the transferability of such sterically hindered groups in inhibitor design.

Original languageEnglish
Pages (from-to)971-980
Number of pages10
JournalChemistry and Biology
Issue number9
StatePublished - Sep 2002


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