Frère J M
Laboratoire d'Enzymologie and Centre d'Ingénierie des Protéines, Institut de Chimie, Université de Liège, Sart Tilman, Belgium.
Mol Microbiol. 1995 May;16(3):385-95. doi: 10.1111/j.1365-2958.1995.tb02404.x.
The efficiency of beta-lactam antibiotics, which are among our most useful chemotherapeutic weapons, is continuously challenged by the emergence of resistant bacterial strains. This is most often due to the production of beta-lactamases by the resistant cells. These enzymes inactivate the antibiotics by hydrolysing the beta-lactam amide bond. The elucidation of the structures of some beta-lactamases by X-ray crystallography has provided precious insights into their catalytic mechanisms and revealed unsuspected similarities with the DD-transpeptidases, the bacterial enzymes which constitute the lethal targets of beta-lactams. Despite numerous kinetic, structural and site-directed mutagenesis studies, we have not completely succeeded in explaining the diversity of the specificity profiles of beta-lactamases and their surprising catalytic power. The solutions to these problems represent the cornerstones on which better antibiotics can be designed, hopefully on a rational basis.
β-内酰胺抗生素是我们最有用的化疗武器之一，但其有效性不断受到耐药菌株出现的挑战。这通常是由于耐药细胞产生β-内酰胺酶所致。这些酶通过水解β-内酰胺酰胺键使抗生素失活。通过X射线晶体学对一些β-内酰胺酶结构的阐明，为其催化机制提供了宝贵的见解，并揭示了与DD-转肽酶意想不到的相似性，DD-转肽酶是构成β-内酰胺致死靶点的细菌酶。尽管进行了大量的动力学、结构和定点诱变研究，但我们尚未完全成功地解释β-内酰胺酶特异性谱的多样性及其惊人的催化能力。这些问题的解决方案是设计更好抗生素的基石，有望基于合理的基础。
