Matagne A, Lamotte-Brasseur J, Frère J M
Centre for Protein Engineering and Laboratoire d'Enzymologie, Université de Liège, Institut de Chimie B6, 4000 Liège (Sart Tilman), Belgium.
Biochem J. 1998 Mar 1;330 ( Pt 2)(Pt 2):581-98. doi: 10.1042/bj3300581.
beta-Lactamases are the main cause of bacterial resistance to penicillins, cephalosporins and related beta-lactam compounds. These enzymes inactivate the antibiotics by hydrolysing the amide bond of the beta-lactam ring. Class A beta-lactamases are the most widespread enzymes and are responsible for numerous failures in the treatment of infectious diseases. The introduction of new beta-lactam compounds, which are meant to be 'beta-lactamase-stable' or beta-lactamase inhibitors, is thus continuously challenged either by point mutations in the ubiquitous TEM and SHV plasmid-borne beta-lactamase genes or by the acquisition of new genes coding for beta-lactamases with different catalytic properties. On the basis of the X-ray crystallography structures of several class A beta-lactamases, including that of the clinically relevant TEM-1 enzyme, it has become possible to analyse how particular structural changes in the enzyme structures might modify their catalytic properties. However, despite the many available kinetic, structural and mutagenesis data, the factors explaining the diversity of the specificity profiles of class A beta-lactamases and their amazing catalytic efficiency have not been thoroughly elucidated. The detailed understanding of these phenomena constitutes the cornerstone for the design of future generations of antibiotics.
β-内酰胺酶是细菌对青霉素、头孢菌素及相关β-内酰胺类化合物产生耐药性的主要原因。这些酶通过水解β-内酰胺环的酰胺键使抗生素失活。A类β-内酰胺酶是分布最广泛的酶，也是导致传染病治疗失败的常见原因。因此，旨在“对β-内酰胺酶稳定”的新型β-内酰胺类化合物或β-内酰胺酶抑制剂，不断受到无处不在的TEM和SHV质粒介导的β-内酰胺酶基因突变，或获得编码具有不同催化特性的β-内酰胺酶新基因的挑战。基于包括临床相关的TEM-1酶在内的几种A类β-内酰胺酶的X射线晶体学结构，已经能够分析酶结构中的特定结构变化如何改变其催化特性。然而，尽管有许多可用的动力学、结构和诱变数据，但解释A类β-内酰胺酶特异性谱多样性及其惊人催化效率的因素尚未得到充分阐明。对这些现象的详细理解是设计下一代抗生素的基石。
