ja9818001_si_001.pdf (218.6 kB)
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
journal contribution
posted on 1998-09-09, 00:00 authored by Laurent Maveyraud, Lionel Mourey, Lakshmi P. Kotra, Jean-Denis Pedelacq, Valérie Guillet, Shahriar Mobashery, Jean-Pierre SamamaBacteria 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 Escherichia coli, 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.