4E3M: Crystal Structure Of Ampc Beta-Lactamase In Complex With A 2-Chloro-4- Tetrazolyl Benzene Sulfonamide Boronic Acid Inhibitor

Fragment-based design was used to guide derivatization of a lead series of beta-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 beta-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 beta-lactamase-based resistance, a key clinical challenge.
PDB ID: 4E3MDownload
MMDB ID: 103322
PDB Deposition Date: 2012/3/9
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 1.44  Å
Source Organism:
Similar Structures:
Biological Unit for 4E3M: monomeric; determined by author
Molecular Components in 4E3M
Label Count Molecule
Protein (1 molecule)
Beta-lactamase(Gene symbol: ampC)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB