DNA 回旋酶和拓扑异构酶 IV 基因突变导致霍乱弧菌 O139 菌株对氟喹诺酮类药物的耐药性增加。
Accumulation of mutations in DNA gyrase and topoisomerase IV genes contributes to fluoroquinolone resistance in Vibrio cholerae O139 strains.
机构信息
State Key Laboratory for Infectious Disease Prevention and Control, Department of Diarrheal Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
出版信息
Int J Antimicrob Agents. 2013 Jul;42(1):72-5. doi: 10.1016/j.ijantimicag.2013.03.004. Epub 2013 May 1.
High resistance rates to nalidixic acid (NAL) in Vibrio cholerae serogroup O139 strains have been found, and ciprofloxacin (CIP) resistance is also observed. In this study, mutations within the quinolone-resistance determining regions (QRDRs) of DNA gyrase and topoisomerase IV from NAL-resistant O139 strains were analysed. The predominant mutation profile was S83I in GyrA in combination with S85L in ParC. In addition, the combination substitutions of D87N in GyrA and D420N in ParE in combination with S83I in GyrA and S85L in ParC as well as D87N in GyrA and P439S in ParE in combination with S83I in GyrA and S85L in ParC were found in the CIP-resistant strains. A series of site-directed mutants comprising D87 in GyrA, D420 in ParE and P439 in ParE were constructed from a wild-type V. cholerae O139 strain carrying the common mutations S83I in GyrA and S85L in ParC. Introduction of the mutation D87N in GyrA increased the CIP minimum inhibitory concentration (MIC) of the mutant strain by nearly 4-fold compared with the initial strain. The second introduction of D420N in ParE further significantly increased the CIP MIC to ca. 23-fold compared with the initial strain. A second introduction of P439S in ParE also increased the CIP MIC by 17-fold. Therefore, it is concluded that the emergence of D87N in GyrA and D420N or P439S in ParE dramatically induces resistance to fluoroquinolones in V. cholerae O139, and the accumulation of multiple mutations in the QRDRs confers significant resistance to fluoroquinolones in V. cholerae.
已发现霍乱弧菌 O139 血清群对萘啶酸（NAL）的耐药率较高，并且还观察到环丙沙星（CIP）耐药性。在这项研究中，分析了 NAL 耐药 O139 菌株中 DNA 回旋酶和拓扑异构酶 IV 的喹诺酮耐药决定区（QRDR）内的突变。主要的突变谱是 GyrA 中的 S83I 与 ParC 中的 S85L 相结合。此外，还发现 CIP 耐药株中 GyrA 中的 D87N 和 ParE 中的 D420N 与 GyrA 中的 S83I 和 ParC 中的 S85L 以及 GyrA 中的 D87N 和 ParE 中的 P439S 与 GyrA 中的 S83I 和 ParC 中的 S85L 相结合。从携带 GyrA 中的 S83I 和 ParC 中的 S85L 常见突变的野生型霍乱弧菌 O139 菌株中构建了包含 GyrA 中的 D87、ParE 中的 D420 和 ParE 中的 P439 的一系列定点突变体。与初始菌株相比，GyrA 中的突变 D87N 的引入使突变株的 CIP 最小抑菌浓度（MIC）增加了近 4 倍。在 ParE 中引入第二个突变 D420N 进一步使 CIP MIC 相对于初始菌株显著增加至约 23 倍。在 ParE 中引入第二个突变 P439S 也使 CIP MIC 增加了 17 倍。因此，可以得出结论，GyrA 中的 D87N 和 ParE 中的 D420N 或 P439S 的出现极大地诱导了霍乱弧菌 O139 对氟喹诺酮类药物的耐药性，而 QRDR 中的多个突变的积累赋予了霍乱弧菌对氟喹诺酮类药物的显著耐药性。
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