新型非氟化喹诺酮类药物PGE 9262932和PGE 9509924对具有DNA旋转酶和拓扑异构酶IV特定突变的金黄色葡萄球菌和肺炎链球菌临床分离株的体外活性。
In vitro activities of novel nonfluorinated quinolones PGE 9262932 and PGE 9509924 against clinical isolates of Staphylococcus aureus and Streptococcus pneumoniae with defined mutations in DNA gyrase and topoisomerase IV.
作者信息
Jones Mark E, Critchley Ian A, Karlowsky James A, Blosser-Middleton Renée S, Schmitz Franz-Josef, Thornsberry Clyde, Sahm Daniel F
机构信息
Focus Technologies, Hilversum, The Netherlands. Focus Technologies, Herndon, Virginia, USA.
出版信息
Antimicrob Agents Chemother. 2002 Jun;46(6):1651-7. doi: 10.1128/AAC.46.6.1651-1657.2002.
Two 8-methoxy nonfluorinated quinolones (NFQs), PGE 9262932 and PGE 9509924, were tested against contemporary clinical isolates of Staphylococcus aureus (n = 122) and Streptococcus pneumoniae (n = 69) with genetically defined quinolone resistance-determining regions (QRDRs). For S. aureus isolates with wild-type (WT) sequences at the QRDRs, the NFQs demonstrated activities 4- to 32-fold more potent (MICs at which 90% of isolates are inhibited [MIC(90)s], 0.03 microg/ml) than those of moxifloxacin (MIC(90), 0.12 microg/ml), gatifloxacin (MIC(90), 0.25 microg/ml), levofloxacin (MIC(90), 0.25 microg/ml), and ciprofloxacin (MIC(90), 1 microg/ml). Against S. pneumoniae isolates with WT sequences at gyrA and parC, the NFQs PGE 9262932 (MIC(90), 0.03 microg/ml) and PGE 9509924 (MIC(90), 0.12 microg/ml) were 8- to 64-fold and 2- to 16-fold more potent, respectively, than moxifloxacin (MIC(90), 0.25 microg/ml), gatifloxacin (MIC(90), 0.5 microg/ml), levofloxacin (MIC(90), 2 microg/ml), and ciprofloxacin (MIC(90), 2 microg/ml). The MICs of all agents were elevated for S. aureus isolates with alterations in GyrA (Glu88Lys or Ser84Leu) and GrlA (Ser80Phe) and S. pneumoniae isolates with alterations in GyrA (Ser81Phe or Ser81Tyr) and ParC (Ser79Phe or Lys137Asn). Fluoroquinolone MICs for S. aureus strains with double alterations in GyrA combined with double alterations in GrlA were > or =32 microg/ml, whereas the MICs of the NFQs for strains with these double alterations were 4 to 8 microg/ml. The PGE 9262932 and PGE 9509924 MICs for the S. pneumoniae isolates did not exceed 0.5 and 1 microg/ml, respectively, even for isolates with GyrA (Ser81Phe) and ParC (Ser79Phe) alterations, for which levofloxacin MICs were > 16 microg/ml. No difference in the frequency of selection of mutations (< 10(-8) at four times the MIC) in wild-type or first-step mutant isolates of S. aureus or S. pneumoniae was detected for the two NFQs. On the basis of their in vitro activities, these NFQ agents show potential for the treatment of infections caused by isolates resistant to currently available fluoroquinolones.
对两种8-甲氧基非氟化喹诺酮类药物（NFQs），即PGE 9262932和PGE 9509924，针对具有基因定义的喹诺酮耐药决定区（QRDRs）的金黄色葡萄球菌（n = 122）和肺炎链球菌（n = 69）的当代临床分离株进行了测试。对于QRDRs具有野生型（WT）序列的金黄色葡萄球菌分离株，NFQs显示出比莫西沙星（MIC(90)，0.12μg/ml）、加替沙星（MIC(90)，0.25μg/ml）、左氧氟沙星（MIC(90)，0.25μg/ml）和环丙沙星（MIC(90)，1μg/ml）强4至32倍的活性（抑制90%分离株的MIC[MIC(90)s]，0.03μg/ml）。对于gyrA和parC具有WT序列的肺炎链球菌分离株，NFQs PGE 9262932（MIC(90)，0.03μg/ml）和PGE 9509924（MIC(90)，0.12μg/ml）分别比莫西沙星（MIC(90)，0.25μg/ml）、加替沙星（MIC(90)，0.5μg/ml）、左氧氟沙星（MIC(90)，2μg/ml）和环丙沙星（MIC(90)，2μg/ml）强8至64倍和2至16倍。对于GyrA（Glu88Lys或Ser84Leu）和GrlA（Ser80Phe）发生改变的金黄色葡萄球菌分离株以及GyrA（Ser81Phe或Ser81Tyr）和ParC（Ser79Phe或Lys137Asn）发生改变的肺炎链球菌分离株，所有药物的MIC均升高。GyrA与GrlA均发生双改变的金黄色葡萄球菌菌株的氟喹诺酮MIC≥32μg/ml，而具有这些双改变的菌株的NFQs MIC为4至8μg/ml。即使对于GyrA（Ser81Phe）和ParC（Ser79Phe）发生改变的肺炎链球菌分离株（其左氧氟沙星MIC>16μg/ml），PGE 9262932和PGE 9509924的MIC分别不超过0.5和1μg/ml。对于两种NFQs，在金黄色葡萄球菌或肺炎链球菌的野生型或第一步突变分离株中，未检测到突变选择频率（在四倍MIC时<10(-8)）的差异。基于它们的体外活性，这些NFQ药物显示出治疗由对当前可用氟喹诺酮耐药的分离株引起的感染的潜力。
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