Genetic Analyses of Mutations Contributing to Fluoroquinolone Resistance in Clinical Isolates ofStreptococcus pneumoniae
Genetic Analyses of Mutations Contributing to Fluoroquinolone Resistance in Clinical Isolates ofStreptococcus pneumoniae
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肺炎链球菌临床分离株中导致氟喹诺酮耐药的突变的遗传分析
DOI：
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发表时间：
2001
影响因子：
4.9
通讯作者：
F. Tenover
中科院分区：
文献类型：
--
作者：
L. Weigel;Gregory J. Anderson;R. Facklam;F. Tenover
通过血清型、抗菌药物敏感性和gyrA、gyrB、parC和帕雷喹诺酮类耐药决定区（QRDRs）的遗传分析，对21株对氟喹诺酮类药物敏感性降低或耐药的肺炎链球菌临床分离株进行了表征。5株菌株对3种或3种以上抗菌药物耐药。在加替沙星、吉非替尼、左氧氟沙星、阿托沙星、氧氟沙星、司帕沙星和曲伐沙星的敏感性特征中，14株分离株对除吉非替尼外的所有氟喹诺酮类药物均具有中度或高度耐药（未指定折点）。氟喹诺酮耐药与血清型或对其他抗菌药物的耐药性无关。这些分离株的QRDRs中的突变比先前报道的体外选择的突变体更异质。八个分离株在ParC/S79和GyrA/S81以外的位点发生了氨基酸变化;几个菌株在gyrB、帕雷或两个位点都含有突变。通过S. pneumoniae R6. gyrB基因突变对加替沙星耐药有重要影响，而对阿托沙星无影响; gyrA基因突变对阿托沙星耐药有重要影响，但对加替沙星无影响，表明两种8-甲氧基喹诺酮类药物的药物-靶点相互作用存在差异。这四个基因内的氨基酸变化位置对耐药性的影响比QRDR突变总数的影响更大。然而，特定突变的影响根据测试的药剂而显著变化。这些数据表明，随着肺炎球菌暴露于新型氟喹诺酮结构，突变的异质性可能会增加，使这类抗菌药物的交叉耐药性预测复杂化。
ABSTRACT Twenty-one clinical isolates of Streptococcus pneumoniae showing reduced susceptibility or resistance to fluoroquinolones were characterized by serotype, antimicrobial susceptibility, and genetic analyses of the quinolone resistance-determining regions (QRDRs) of gyrA,gyrB, parC, and parE. Five strains were resistant to three or more classes of antimicrobial agents. In susceptibility profiles for gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, ofloxacin, sparfloxacin, and trovafloxacin, 14 isolates had intermediate- or high-level resistance to all fluoroquinolones tested except gemifloxacin (no breakpoints assigned). Fluoroquinolone resistance was not associated with serotype or with resistance to other antimicrobial agents. Mutations in the QRDRs of these isolates were more heterogeneous than those previously reported for mutants selected in vitro. Eight isolates had amino acid changes at sites other than ParC/S79 and GyrA/S81; several strains contained mutations in gyrB, parE, or both loci. Contributions to fluoroquinolone resistance by individual amino acid changes, including GyrB/E474K, ParE/E474K, and ParC/A63T, were confirmed by genetic transformation of S. pneumoniae R6. Mutations in gyrB were important for resistance to gatifloxacin but not moxifloxacin, and mutation of gyrAwas associated with resistance to moxifloxacin but not gatifloxacin, suggesting differences in the drug-target interactions of the two 8-methoxyquinolones. The positions of amino acid changes within the four genes affected resistance more than did the total number of QRDR mutations. However, the effect of a specific mutation varied significantly depending on the agent tested. These data suggest that the heterogeneity of mutations will likely increase as pneumococci are exposed to novel fluoroquinolone structures, complicating the prediction of cross-resistance within this class of antimicrobial agents.
影响因子：
10.5
作者：
E. Zechiedrich;N. Cozzarelli
通讯作者：
E. Zechiedrich;N. Cozzarelli