1. J Am Chem Soc. 2010 Mar 3;132(8):2558-60.

Cyclobutanone Analogues of beta-Lactams Revisited: Insights into Conformational
Requirements for Inhibition of Serine- and Metallo-beta-Lactamases.

Johnson JW, Gretes M, Goodfellow VJ, Marrone L, Heynen ML, Strynadka NC,
Dmitrienko GI.

Department of Chemistry, University of Waterloo, 200 University Avenue West,
Waterloo, Ontario, Canada N2L 3G1, and Department of Biochemistry and Molecular
Biology and the Center for Blood Research, University of British Columbia, 2350
Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.

The most important mode of bacterial resistance to beta-lactam antibiotics is the
expression of beta-lactamases. New cyclobutanone analogues of penams and penems
have been prepared and evaluated for inhibition of class A, B, C, and D
beta-lactamases. Inhibitors which favor conformations in which the C4 carboxylate
is equatorial were found to be more potent than those in which the carboxylate is
axial, and molecular modeling studies with enzyme-inhibitor complexes indicate
that an equatorial orientation of the carboxylate is required for binding to
beta-lactamases. An X-ray structure of OXA-10 complexed with a cyclobutanone
confirms that a serine hemiketal is formed in the active site and that the
inhibitor adopts the exo envelope. An unsaturated penem analogue was also found
to enhance the potency of meropenem against carbapenem-resistant MBL-producing
strains of Chryseobacterium meningosepticum and Stenotrophomonas maltophilia .
These cyclobutanones represent the first type of reversible inhibitors to show
moderate (low micromolar) inhibition of both serine- and metallo-beta-lactamases 
and should be considered for further development into practical inhibitors.

PMID: 20141132 [PubMed - in process]