4E3N

Crystal structure of AmpC beta-lactamase in complex with a 2-trifluoromethyl-4-tetrazolyl benzene sulfonamide boronic acid inhibitor

Summary for 4E3N

• Entry DOI: 10.2210/pdb4e3n/pdb
• Related: 4E3I 4E3J 4E3K 4E3L 4E3M 4E3O
• Descriptor: Beta-lactamase, [({[4-(1H-tetrazol-5-yl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)methyl]boronic acid, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: ampc beta-lactamase, class c, cephalosporinase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Escherichia coli
• Cellular location: Periplasm: P00811
• Total number of polymer chains: 2
• Total formula weight: 80162.90

Authors

Eidam, O.,Shoichet, B.K. (deposition date: 2012-03-09, release date: 2012-09-26, Last modification date: 2023-09-13)

Primary citation

Eidam, O.,Romagnoli, C.,Dalmasso, G.,Barelier, S.,Caselli, E.,Bonnet, R.,Shoichet, B.K.,Prati, F.
Fragment-guided design of subnanomolar beta-lactamase inhibitors active in vivo.
Proc.Natl.Acad.Sci.USA, 109:17448-17453, 2012

PubMed 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 K(i) 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 Escherichia 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.

PubMed: 23043117
DOI: 10.1073/pnas.1208337109

Experimental method

X-RAY DIFFRACTION (1.49 Å)