4gd8

Publication Abstract from PubMed

Bacterial beta-lactamase enzymes are in large part responsible for the decreased ability of beta-lactam antibiotics to combat infections. The inability to overcome beta-lactamase mediated resistance spurred the development of inhibitors with penems and penam sulfones being amongst the most potent and broad spectrum mechanism-based inactivators. These inhibitors form covalent, "suicide-type" inhibitory intermediates that are attached to the catalytic S70 residue. To further probe the details of the mechanism of beta-lactamase inhibition by these novel compounds, we determined the crystal structures of SHV-1 bound with penem 1, and penam sulfones SA1-204 and SA3-53. Comparison with each other and with previously determined crystal structures of members of these classes of inhibitors suggests that the final conformation of the covalent adduct can vary greatly amongst the complex structures. In contrast, a common theme of carbonyl conjugation as a mechanism to avoid deacylation emerges despite that the penem and penam sulfone inhibitors form different types of intermediates. The detailed insights gained from this study could be used to further improve new mechanism-based inhibitors of these common class A serine beta-lactamases.

Structures of SHV-1 beta-lactamase with penem and penam sulfone inhibitors that form cyclic intermediates stabilized by carbonyl conjugation.,Ke W, Pattanaik P, Bethel CR, Sheri A, Buynak JD, Bonomo RA, van den Akker F PLoS One. 2012;7(11):e49035. doi: 10.1371/journal.pone.0049035. Epub 2012 Nov 8. PMID:23145056^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.