Structural Basis for Clinical Longevity of Carbapenem Antibiotics in the Face of Challenge by the Common Class A β-Lactamases from the Antibiotic-Resistant Bacteria

Bacteria resistant to antibiotics are being selected in a relatively short time, and cases of infections resistant to treatment by all known antibiotics are being identified at alarming rates. The primary mechanism for resistance to β-lactam antibiotics is the catalytic function of β-lactamases. However, imipenem (a β-lactam) resists the action of most β-lactamases and is virtually the last effective agent against the vancomycin-resistant Gram-positive bacteria, as well as against multiple antibiotic-resistant Gram-negative organisms. Here, we report the crystal structure, to 1.8 Å resolution, of an acyl−enzyme intermediate for imipenem bound to the TEM-1 β-lactamase from <i>Escherichia coli</i>, the parent enzyme of 67 clinical variants. The structure indicates an unprecedented conformational change for the complex which accounts for the ability of this antibiotic to resist hydrolytic deactivation by β-lactamases. Computational molecular dynamics underscored the importance of the motion of the acyl−enzyme intermediate, which may be a general feature for catalysis by these enzymes.