Mechanisms of fluoroquinolone resistance: An update 1994-1998
Mechanisms of fluoroquinolone resistance: An update 1994-1998
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DOI：
10.2165/00003495-199958002-00003
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发表时间：
1999-01-01
期刊：
影响因子：
11.5
通讯作者：
Piddock, LJV
中科院分区：
文献类型：
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作者：
Piddock, LJV
氟喹诺酮耐药性是由靶标变化（DNA 旋转酶和/或拓扑异构酶 IV）和/或细胞内积累减少介导的。 DNA 拓扑异构酶 IV 的基因 (gyrA/gyrB/parC/parE) 和蛋白质在核苷酸和氨基酸序列水平上与 DNA 旋转酶的基因 (gyrA/gyrB/parC/parE) 和蛋白质显示出极大的相似性。研究表明，gyrA 和 parC 内存在突变热点，称为喹诺酮耐药决定区 (QRDR)。根据大肠杆菌坐标，最有利于引起对喹诺酮类药物敏感性降低和/或完全耐药的热点是gyrA的丝氨酸83和天冬氨酸87，以及parC的丝氨酸79和天冬氨酸83。几乎没有任何细菌的 gyrB 或 parE/grlB 突变被描述。氟喹诺酮类药物的外流是这些药物蓄积减少的主要原因；对于金黄色葡萄球菌，参与诺氟沙星耐药的外排泵是 NorA，而对于肺炎链球菌，涉及诺氟沙星耐药的外排泵是 PmrA。通过分析在存在和不存在外排抑制剂利血平的情况下获得的最低抑菌浓度 (MIC) 数据，结果表明，高达 50% 的耐环丙沙星肺炎链球菌临床分离株可能具有增强的外排。这表明外排可能是该物种临床耐药的重要机制。在铜绿假单胞菌中，一些外排操纵子已在遗传和生化方面得到证实。这些操纵子由 mex (Multiple EffluX) 基因编码：mexAmexB-oprM、mexCD-OprJ 系统和 mexEF-oprN 系统。大肠杆菌外排泵是 acrAB-tolC 系统。 mar 操纵子和 sox 操纵子均可引起多种抗生素耐药性。研究表明，导致转录激活因子 marA 和 soxS 表达增加的突变会影响多种不同基因的表达，包括 ompF 和 acrAB。最终结果是 OmpF 的表达减少，并且能够进入细胞的药物少得多； acrAB 的表达增加，从而增强细胞的流出。
Fluoroquinolone resistance is mediated by target changes (DNA gyrase and/ or topoisomerase IV) and/or decreased intracellular accumulation. The genes (gyrA/gyrB/parC/parE) and proteins of DNA topoisomerase IV show great similarity, both at the nucleotide and amino acid sequence level to those of DNA gyrase. It has been shown that there are hotspots, called the quinolone resistance determining region (QRDR), for mutations within gyrA and parC. Based on the Escherichia coli co-ordinates, the hotspots most favoured for giving rise to decreased susceptibility and/or full resistance to quinolones are at serine 83 and aspartate 87 of gyrA, and at serine 79 and aspartate 83 for parC. Few mutations in gyrB or parE/grlB of any bacteria have been described. Efflux of fluoroquinolones is the major cause of decreased accumulation of these agents; for Staphylococcus aureus, the efflux pump involved in norfloxacin resistance is NorA, and for Streptococcus pneumoniae, PmrA. By analysis of minimum inhibitory concentration (MIC) data derived in the presence and absence of the efflux inhibitor reserpine, it has been shown that up to 50% of ciprofloxacin-resistant clinical isolates of S. pneumoniae may possess enhanced efflux. This suggests that efflux may be an important mechanism of clinical resistance in this species. In Pseudomonas aeruginosa, several efflux operons have been demonstrated genetically and biochemically. These operons are encoded by mex (Multiple EffluX) genes: mexAmexB-oprM, mexCD-OprJ system and mexEF-oprN system. The E. coli efflux pump is the acrAB-tolC system. Both the mar operon and the sox operon can give rise to multiple antibiotic resistance. It has been shown that mutations giving rise to increased expression of the transcriptional activators marA and soxS affect the expression of a variety of different genes, including ompF and acrAB. The net result is that expression of OmpF is reduced and much less drug is able to enter the cell; expression of acrAB is increased, enhancing efflux from the cell.