Key role of Mfd in the development of fluoroquinolone resistance in Campylobacter jejuni.
Key role of Mfd in the development of fluoroquinolone resistance in Campylobacter jejuni.
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MFD在空肠弯曲杆菌中氟喹诺酮耐药性发展中的关键作用。
DOI：
10.1371/journal.ppat.1000083
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发表时间：
2008-06-06
期刊：
影响因子：
6.7
通讯作者：
Zhang, Qijing
中科院分区：
文献类型：
--
作者：
Han, Jing;Sahin, Orhan;Barton, Yi-Wen;Zhang, Qijing
空肠弯曲杆菌是一种主要的食源性致病菌，是人类小肠结肠炎的常见病原体。氟喹诺酮类药物是临床治疗弯曲菌病等肠道感染的关键抗生素，但在抗生素选择压力下极易出现耐氟喹诺酮弯曲菌。为了了解耐氟喹诺酮弯曲杆菌的形成机制，我们使用DNA芯片比较了空肠C.在环丙沙星存在和不存在时的基因表达谱。我们的分析显示，多个基因在环丙沙星的超抑制浓度下表现出显著的表达变化。最重要的是，环丙沙星诱导了mfd的表达，mfd编码一种参与链特异性DNA修复的转录修复偶联因子。mfd基因的突变导致环丙沙星耐药的自发突变率降低约100倍，而mfd基因的过表达提高了突变频率。此外，在使用氟喹诺酮类药物的培养基或鸡中，空肠C. mfd的缺失显著减少了耐氟喹诺酮类药物弯曲杆菌的发展。这些发现表明，Mfd对弯曲杆菌的氟喹诺酮类耐药性的发展很重要，揭示了Mfd在促进突变频率方面的先前未被认识到的功能，并确定了减少氟喹诺酮类耐药性弯曲杆菌出现的潜在分子靶点。空肠弯曲杆菌（Campylobacter jejuni）是一种食源性细菌病原体，是人类常见的胃肠道疾病病原体。弯曲杆菌中抗生素耐药性的发展，特别是对氟喹诺酮（一种广谱抗菌素）的耐药性，危及临床治疗并构成重大公共卫生威胁。弯曲杆菌为何对氟喹诺酮类药物具有高度适应性，以及它如何获得与氟喹诺酮类药物耐药性相关的突变，目前尚不清楚。了解耐药性发展的分子机制将有助于我们减少氟喹诺酮耐药弯曲杆菌的出现。利用DNA微阵列和其他分子方法，以及动物实验，我们发现Mfd在促进弯曲杆菌自发突变和氟喹诺酮类药物耐药性发展中的关键作用。Mfd是一种参与DNA修复的转录修复偶联因子，以前并不知道它在促进突变产生抗生素耐药性方面的作用。我们的发现不仅揭示了Mfd的新功能，而且为减少氟喹诺酮耐药弯曲杆菌的出现提供了潜在的分子靶点。
Campylobacter jejuni is a major food-borne pathogen and a common causative agent of human enterocolitis. Fluoroquinolones are a key class of antibiotics prescribed for clinical treatment of enteric infections including campylobacteriosis, but fluoroquinolone-resistant Campylobacter readily emerges under the antibiotic selection pressure. To understand the mechanisms involved in the development of fluoroquinolone-resistant Campylobacter, we compared the gene expression profiles of C. jejuni in the presence and absence of ciprofloxacin using DNA microarray. Our analysis revealed that multiple genes showed significant changes in expression in the presence of a suprainhibitory concentration of ciprofloxacin. Most importantly, ciprofloxacin induced the expression of mfd, which encodes a transcription-repair coupling factor involved in strand-specific DNA repair. Mutation of the mfd gene resulted in an approximately 100-fold reduction in the rate of spontaneous mutation to ciprofloxacin resistance, while overexpression of mfd elevated the mutation frequency. In addition, loss of mfd in C. jejuni significantly reduced the development of fluoroquinolone-resistant Campylobacter in culture media or chickens treated with fluoroquinolones. These findings indicate that Mfd is important for the development of fluoroquinolone resistance in Campylobacter, reveal a previously unrecognized function of Mfd in promoting mutation frequencies, and identify a potential molecular target for reducing the emergence of fluoroquinolone-resistant Campylobacter. As a food-borne bacterial pathogen, Campylobacter jejuni is a common causative agent of gastrointestinal illnesses in humans. Development of antibiotic resistance in Campylobacter, especially to fluoroquinolone (a broad-spectrum antimicrobial), compromises clinical treatments and presents a major public health threat. It is not well understood why Campylobacter is highly adaptable to fluoroquinolone treatment or how it acquires mutations associated with fluoroquinolone resistance. Understanding the molecular mechanisms involved in the resistance development will help us to reduce the emergence of fluoroquinolone-resistant Campylobacter. Using DNA microarray and other molecular methods, as well as animal studies, we uncovered the key role of Mfd in promoting spontaneous mutations and development of fluoroquinolone resistance in Campylobacter. Mfd is a transcription-repair coupling factor involved in DNA repair and was not previously known for its role in promoting mutations conferring antibiotic resistance. Our findings not only reveal a novel function of Mfd, but also provide a potential molecular target for reducing the emergence of fluoroquinolone-resistant Campylobacter.
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