Calvez Philippe, Breukink Eefjan, Roper David I, Dib Mélanie, Contreras-Martel Carlos, Zapun André
From the Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS, 38044 Grenoble, France.
the Department of Chemical Biology and Organic Chemistry, Institute of Biomembranes, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht 3584 CH, The Netherlands, and.
J Biol Chem. 2017 Feb 17;292(7):2854-2865. doi: 10.1074/jbc.M116.764696. Epub 2017 Jan 6.
Pneumococcus resists β-lactams by expressing variants of its target enzymes, the penicillin-binding proteins (PBPs), with many amino acid substitutions. Up to 10% of the sequence can be modified. These altered PBPs have a much reduced reactivity with the drugs but retain their physiological activity of cross-linking the peptidoglycan, the major constituent of the bacterial cell wall. However, because β-lactams are chemical and structural mimics of the natural substrate, resistance mediated by altered PBPs raises the following paradox: how PBPs that react poorly with the drugs maintain a sufficient level of activity with the physiological substrate. This question is addressed for the first time in this study, which compares the peptidoglycan cross-linking activity of PBP2b from susceptible and resistant strains with their inhibition by different β-lactams. Unexpectedly, the enzymatic activity of the variants did not correlate with their antibiotic reactivity. This finding indicates that some of the numerous amino acid substitutions were selected to restore a viable level of enzymatic activity by a compensatory molecular mechanism.
肺炎球菌通过表达其靶酶青霉素结合蛋白（PBPs）的变体来抵抗β-内酰胺类药物，这些变体有许多氨基酸替换。其序列中高达10%可被修饰。这些改变后的PBPs与药物的反应性大大降低，但保留了其交联肽聚糖（细菌细胞壁的主要成分）的生理活性。然而，由于β-内酰胺类药物是天然底物的化学和结构模拟物，由改变后的PBPs介导的耐药性引发了以下悖论：与药物反应不佳的PBPs如何与生理底物保持足够水平的活性。本研究首次解决了这个问题，该研究比较了敏感菌株和耐药菌株中PBP2b的肽聚糖交联活性及其被不同β-内酰胺类药物抑制的情况。出乎意料的是，变体的酶活性与其抗生素反应性不相关。这一发现表明，众多氨基酸替换中的一些是通过补偿性分子机制被选择来恢复可行的酶活性水平的。
