Fragment-based design was used to guide derivatization of a lead series of β-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a Ki of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with β-lactamase-expressing E. coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome β-lactamase-based resistance, a key clinical challenge.

Fragment-guided Design of Subnanomolar β-Lactamase Inhibitors Active in vivo / O., Eidam; Romagnoli, Chiara; G., Dalmasso; S., Barelier; Caselli, Emilia; R., Bonnet; B. K., Shoichet; Prati, Fabio. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - STAMPA. - 109:(2012), pp. 17448-17453. [10.1073/pnas.1208337109]

Fragment-guided Design of Subnanomolar β-Lactamase Inhibitors Active in vivo

ROMAGNOLI, Chiara;CASELLI, Emilia;PRATI, Fabio
2012

Abstract

Fragment-based design was used to guide derivatization of a lead series of β-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a Ki of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with β-lactamase-expressing E. coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome β-lactamase-based resistance, a key clinical challenge.
2012
109
17448
17453
Fragment-guided Design of Subnanomolar β-Lactamase Inhibitors Active in vivo / O., Eidam; Romagnoli, Chiara; G., Dalmasso; S., Barelier; Caselli, Emilia; R., Bonnet; B. K., Shoichet; Prati, Fabio. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - STAMPA. - 109:(2012), pp. 17448-17453. [10.1073/pnas.1208337109]
O., Eidam; Romagnoli, Chiara; G., Dalmasso; S., Barelier; Caselli, Emilia; R., Bonnet; B. K., Shoichet; Prati, Fabio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/773089
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