beta-lactamases are the most widespread resistance mechanism to beta-lactam antibiotics, such as the penicillins and the cephalosporins. In an effort to combat these enzymes, a combination of stereoselective organic synthesis, enzymology, microbiology, and X-ray crystallography was used to design and evaluate new carboxyphenyl-glycylboronic acid transition-state analogue inhibitors of the class C beta-lactamase AmpC. The new compounds improve inhibition by over 2 orders of magnitude compared to analogous glycylboronic acids, with K-1 values as low as 1 nM. On the basis of the differential binding of different analogues, the introduced carboxylate alone contributes about 2.1 kcal/mol in affinity. This carboxylate corresponds to the ubiquitous C3(4)'carboxylate of beta-lactams, and this energy represents the first thermodynamic measurement of the importance of this group in molecular recognition by class C beta-lactamases. The structures of AmpC in complex with two of these inhibitors were determined by X-ray crystallography at 1.72 and 1.83 Angstrom resolution. These structures suggest a structural basis for the high affinity of the new compounds and provide templates for further design. The highest affinity inhibitor was 5 orders of magnitude more selective for AmpC than for characteristic serine proteases, such as chymotrypsin. This inhibitor reversed the resistance of clinical pathogens to the third generation cephalosporin ceftazidime; it may serve as a lead compound for drug discovery to combat bacterial resistance to beta-lactam antibiotics.
Nanomolar inhibitors of AmpC beta-lactamase / Morandi, Federica; Caselli, Emilia; Morandi, Stefania; P. J., Focia; J., Blazquez; B. K., Shoichet; Prati, Fabio. - In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - ISSN 0002-7863. - STAMPA. - 125(2003), pp. 685-695.
Data di pubblicazione: | 2003 |
Titolo: | Nanomolar inhibitors of AmpC beta-lactamase |
Autore/i: | Morandi, Federica; Caselli, Emilia; Morandi, Stefania; P. J., Focia; J., Blazquez; B. K., Shoichet; Prati, Fabio |
Autore/i UNIMORE: | |
Rivista: | |
Volume: | 125 |
Pagina iniziale: | 685 |
Pagina finale: | 695 |
Codice identificativo ISI: | WOS:000180468900026 |
Codice identificativo Scopus: | 2-s2.0-0037460187 |
Codice identificativo Pubmed: | 12526668 |
Citazione: | Nanomolar inhibitors of AmpC beta-lactamase / Morandi, Federica; Caselli, Emilia; Morandi, Stefania; P. J., Focia; J., Blazquez; B. K., Shoichet; Prati, Fabio. - In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - ISSN 0002-7863. - STAMPA. - 125(2003), pp. 685-695. |
Tipologia | Articolo su rivista |
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