STRUCTURAL BASIS FOR CLINICAL LONGEVITY OF CARBAPENEM ANTIBIOTICS IN THE FACE OF CHALLENGE BY THE COMMON CLASS-A BETA-LACTAMASES FROM THE ANTIBIOTIC-RESISTANT BACTERIA

Bacteria resistant to antibiotics are being selected in a relatively s hort time, and cases of infections resistant to treatment by all known antibiotics are being identified at alarming rates. The primary mecha nism for resistance to beta-lactam antibiotics is the catalytic functi on of beta-lactamases. However, imipenem (a beta-lactam) resists the a ction of most beta-lactamases and is virtually the last effective agen t against the vancomycin-resistant Gram-positive bacteria, as well as against multiple antibiotic-resistant Gram-negative organisms. Here, w e report the crystal structure, to 1.8 Angstrom resolution, of an acyl -enzyme intermediate for imipenem bound to the TEM-1 beta-lactamase fr om Escherichia coil, the parent enzyme of 67 clinical variants. The st ructure indicates an unprecedented conformational change for the compl ex which accounts for the ability of this antibiotic to resist hydroly tic deactivation by beta-lactamases. Computational molecular dynamics underscored the importance of the motion of the acyl-enzyme intermedia te, which may be a general feature for catalysis by these enzymes.