结核分枝杆菌
抗生素
内酰胺
微生物学
肺结核
化学
医学
生物
立体化学
病理
作者
Eva Maria Steiner,Günter Schneider,R. Schnell
出处
期刊:FEBS Journal
[Wiley]
日期:2017-02-08
卷期号:284 (5): 725-741
被引量:35
摘要
β-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 a therapeutic target. Peptidoglycan stability in Mycobacterium tuberculosis, especially during infection, relies on the nonconventional peptide cross-links formed by l,d-transpeptidases. These enzymes are known to be inhibited by β-lactams, primarily carbapenems, leading to a stable covalent modification at the enzyme active site. A panel of 16 β-lactam 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 three to four time 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 β-OH-butyryl adduct bound at the catalytic cysteine residue. The crystal structure of LdtMt2 at 1.54 Å 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.Structural data are available in Protein Data Bank under the accession numbers 5LB1 and 5LBG.
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