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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

Abstract : 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-lactam antibiotics is the catalytic function of-lactamases. However, imipenem (a-lactam) resists the action of most-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-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-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. Assuming that the current efforts in the pharmaceutical companies toward discovery and development of novel antibiotics are successful, the use of these new agents would inevitably select for resistance in microbial populations in a relatively short time.
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https://hal-cnrs.archives-ouvertes.fr/hal-03004592
Contributor : Lionel Mourey Connect in order to contact the contributor
Submitted on : Friday, November 20, 2020 - 4:45:19 PM
Last modification on : Wednesday, October 20, 2021 - 3:44:05 AM

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Laurent Maveyraud, Lionel Mourey, Lakshmi Kotra, Jean-Denis Pedelacq, Valérie Guillet, et al.. 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 of the American Chemical Society, American Chemical Society, 1998, 120 (38), pp.9748-9752. ⟨10.1021/ja9818001⟩. ⟨hal-03004592⟩

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