Williamson R, Collatz E, Gutmann L
Presse Med. 1986 Dec 20;15(46):2282-9.
The mode of action of beta-lactam antibiotics, and the non-enzymatic resistance mechanisms to their activity, are intimately linked to the structure and biosynthesis of the bacterial cell wall. The bacteriostatic effect of beta-lactam antibiotics is related to their various interactions and concomitant inhibition of essential enzymes (transpeptidases, carboxypeptidases) involved in the terminal stages of peptidoglycan biosynthesis. These cytoplasmic membrane-associated target enzymes bind the antibiotics covalently, and hence are known as penicillin-binding proteins (PBPs). The bactericidal effect of these antibiotics is due to a second step following on from the inhibition of cell division and growth, in which the activation of an autolytic system causes cell death. Resistance to beta-lactam antibiotics in Gram-positive bacteria, in the absence of a beta-lactamase, is due to various modifications of the PBPs. Such mechanisms are often found in enterococci, pneumococcus, ans staphylococci. With Gram-negative bacteria such modifications of PBPs are only a rare basis for resistance. The presence of an outer membrane brings another factor into the activity of beta-lactam antibiotics, which is the facility with the antibiotics can diffuse through specialised proteins termed porins. It is generally a modification of the amounts of these proteins, or some other components of the outer membrane, which causes the non-enzymatic mechanism of resistance, particularly in species such as Klebsiella, Enterobacter, Serratia and Pseudomonas.
β-内酰胺类抗生素的作用方式及其对其活性的非酶促耐药机制与细菌细胞壁的结构和生物合成密切相关。β-内酰胺类抗生素的抑菌作用与其各种相互作用以及对参与肽聚糖生物合成终末阶段的必需酶（转肽酶、羧肽酶）的协同抑制有关。这些与细胞质膜相关的靶酶与抗生素共价结合，因此被称为青霉素结合蛋白（PBPs）。这些抗生素的杀菌作用是由于在抑制细胞分裂和生长之后的第二步，其中自溶系统的激活导致细胞死亡。在没有β-内酰胺酶的情况下，革兰氏阳性菌对β-内酰胺类抗生素的耐药性是由于PBPs的各种修饰。这种机制常见于肠球菌、肺炎球菌和葡萄球菌中。对于革兰氏阴性菌，PBPs的这种修饰只是耐药的罕见原因。外膜的存在给β-内酰胺类抗生素的活性带来了另一个因素，即抗生素通过称为孔蛋白的特殊蛋白质扩散的难易程度。通常是这些蛋白质的数量或外膜的其他一些成分的改变导致了非酶促耐药机制，特别是在克雷伯菌属、肠杆菌属、沙雷菌属和假单胞菌属等菌种中。
