Effects of NorA inhibitors on in vitro antibacterial activities and postantibiotic effects of levofloxacin, ciprofloxacin, and norfloxacin in genetically related strains of Staphylococcus aureus
Effects of NorA inhibitors on in vitro antibacterial activities and postantibiotic effects of levofloxacin, ciprofloxacin, and norfloxacin in genetically related strains of Staphylococcus aureus
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DOI：
10.1128/aac.43.2.335
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发表时间：
1999-02-01
影响因子：
4.9
通讯作者：
Rybak, MJ
中科院分区：
文献类型：
--
作者：
Aeschlimann, JR;Dresser, LD;Rybak, MJ
诺拉A是一种膜相关的多药外排蛋白，可以降低金黄色葡萄球菌对氟喹诺酮类药物的敏感性。为了确定诺拉A抑制剂对氟喹诺酮类药物药效学的影响，我们评估了左氧氟沙星、环丙沙星和诺氟沙星在有和没有各种诺拉A抑制剂的情况下对三种遗传相关的金黄色葡萄球菌菌株的活性。金黄色葡萄球菌（SA 1199，野生型; SA 1199 B，具有grlA突变的诺拉A超生产菌株;和SA 1199-3，诱导性超生产诺拉A的菌株）的抗感染性试验、时间-杀灭曲线和抗生素后效应（PAE）方法，左氧氟沙星对所有三种菌株具有最有效的活性，并且受加入诺拉A抑制剂的影响最小。相反，利血平、奥美拉唑和兰索拉唑使SA 1199的环丙沙星和诺氟沙星MIC和MBC降低4倍，使SA 1199 B和SA 1199-3降低4- 16倍。或兰索拉唑可使左氧氟沙星对SA 1199-3的单药活性增加2 log（10）CFU/ml，并增加诺氟沙星和环丙沙星对所有三种菌株的活性0.5至4 log（10）CFU/ml。利血平和奥美拉唑使SA 1199、SA 1199 B和SA 1199-3上的诺氟沙星PAE分别从0.9、0.6和0.2 h增加至2.5 - 4.5、1.1 - 1.3和0.4 - 1.1 h;环丙沙星观察到类似的作用。利血平和奥美拉唑仅增加SA 1199 B的左氧氟沙星PAE（分别从1.6小时增加至5.0小时和3.1小时）。总之，诺拉抑制剂显著提高了亲水性更强的氟喹诺酮类药物（诺氟沙星和环丙沙星）的活性。这些化合物可能恢复这些氟喹诺酮类药物对金黄色葡萄球菌耐药菌株的活性，或者可能潜在地增强其对敏感菌株的活性。
NorA is a membrane-associated multidrug efflux protein that can decrease susceptibility to fluoroquinolones in Staphylococcus aureus, To determine the effect of NorA inhibition on the pharmacodynamics of fluoroquinolones, we evaluated the activities of levofloxacin, ciprofloxacin, and norfloxacin with and without various NorA inhibitors against three genetically related strains of S. aureus (SA 1199, the wild-type; SA 1199B, a NorA hyperproducer with a grlA mutation; and SA 1199-3, a strain that inducibly hyperproduces NorA) using susceptibility testing, time-kill curves, and postantibiotic effect (PAE) methods, Levofloxacin had the most potent activity against all three strains and,vas minimally affected by addition of NorA inhibitors. In contrast, reserpine, omeprazole, and lansoprazole produced 4-fold decreases in ciprofloxacin and norfloxacin MICs and MBCs for SA 1199 and 4- to 16-fold decreases for both SA 1199B and SA 1199-3, In time-kill experiments reserpine, omeprazole, or lansoprazole increased levofloxacin activity against SA 1199-3 alone by 2 log(10) CFU/ml and increased norfloxacin and ciprofloxacin activities against all three strains by 0.5 to 4 log(10) CFU/ml. Reserpine and omeprazole increased norfloxacin PAEs on SA 1199, SA 1199B, and SA 1199-3 from 0.9, 0.6, and 0.2 h to 2.5 to 4.5, 1.1 to 1.3, and 0.4 to 1.1 h, respectively; similar effects were observed with ciprofloxacin. Reserpine and omeprazole increased the levofloxacin PAE only on SA 1199B (from 1.6 to 5.0 and 3.1 h, respectively). In conclusion, the NorA inhibitors dramatically improved the activities of the more hydrophilic fluoroquinolones (norfloxacin and ciprofloxacin), These compounds may restore the activities of these fluoroquinolones against resistant strains of S, aureus or may potentially enhance their activities against sensitive strains.