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Publication Abstract from PubMed

beta-lactam antibiotics represent a novel direction in the chemotherapy of tuberculosis that brings the peptidoglycan layer of the complex mycobacterial cell wall in focus as therapeutic target. Peptidoglycan stability in Mycobacterium tuberculosis especially during infection relies on the non-conventional peptide cross-links formed by L,D-transpeptidases. These enzymes are known to be inhibited by beta-lactams, primarily carbapenems, leading to a stable covalent modification at the enzyme active site. A panel of sixteen beta-lactams antibiotics was characterized by inhibition kinetics, mass spectrometry and x-ray crystallography to identify efficient compounds and study their action on the essential transpeptidase LdtMt2 . Members of the carbapenem class displayed fast binding kinetics, but faropenem, a penem type compound showed a 3-4 times higher rate in the adduct formation. In three cases mass spectrometry indicated that carbapenems may undergo decarboxylation, while faropenem decomposition following the acylation step results in a small 87 Da beta-OH-butyryl adduct bound at the catalytic cysteine residue. The crystal structure of LdtMt2 at 1.54 A resolution with this fragment bound revealed that the protein adopts a closed conformation that shields the thioester bond from the solvent, which is in line with the high stability of this dead-end complex observed also in biochemical assays. This article is protected by copyright. All rights reserved.

Binding and processing of beta-lactam antibiotics by the transpeptidase LdtMt2 from Mycobacterium tuberculosis.,Steiner EM, Schneider G, Schnell R FEBS J. 2017 Jan 11. doi: 10.1111/febs.14010. PMID:28075068^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.