FEMS Microbiol Rev. 2017 May 1;41(3):430-449. doi: 10.1093/femsre/fux007.
The major targets for antibiotics in staphylococci are (i) the cell envelope, (ii) the ribosome and (iii) nucleic acids. Several novel targets emerged from recent targeted drug discovery programmes including the ClpP protease and FtsZ from the cell division machinery. Resistance can either develop by horizontal transfer of resistance determinants encoded by mobile genetic elements viz plasmids, transposons and the staphylococcal cassette chromosome or by mutations in chromosomal genes. Horizontally acquired resistance can occur by one of the following mechanisms: (i) enzymatic drug modification and inactivation, (ii) enzymatic modification of the drug binding site, (iii) drug efflux, (iv) bypass mechanisms involving acquisition of a novel drug-resistant target, (v) displacement of the drug to protect the target. Acquisition of resistance by mutation can result from (i) alteration of the drug target that prevents the inhibitor from binding, (ii) derepression of chromosomally encoded multidrug resistance efflux pumps and (iii) multiple stepwise mutations that alter the structure and composition of the cell wall and/or membrane to reduce drug access to its target. This review focuses on development of resistance to currently used antibiotics and examines future prospects for new antibiotics and informed use of drug combinations.
(i) 细胞壁，(ii) 核糖体和 (iii) 核酸。最近的靶向药物发现计划出现了一些新的靶点，包括来自细胞分裂机制的 ClpP 蛋白酶和 FtsZ。耐药性可以通过水平转移由移动遗传元件（如质粒、转座子和葡萄球菌盒式染色体）编码的耐药决定因素，或通过染色体基因的突变而产生。水平获得的耐药性可以通过以下机制之一发生：(i) 酶促药物修饰和失活，(ii) 药物结合部位的酶修饰，(iii) 药物外排，(iv) 涉及获得新的耐药靶标的旁路机制，(v) 置换药物以保护靶标。通过突变获得耐药性可能是由于：(i) 改变药物靶标，阻止抑制剂结合，(ii) 染色体编码的多药耐药外排泵的去阻遏，以及 (iii) 改变细胞壁和/或膜的结构和组成以减少药物到达其靶标的多个逐步突变。这篇综述重点介绍了目前使用的抗生素的耐药性发展，并探讨了新抗生素的未来前景和药物联合使用的明智选择。
