The plasmid-borne quinolone resistance protein QnrB, a novel DnaA-binding protein, increases the bacterial mutation rate by triggering DNA replication stress
The plasmid-borne quinolone resistance protein QnrB, a novel DnaA-binding protein, increases the bacterial mutation rate by triggering DNA replication stress
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质粒携带的喹诺酮抗性蛋白 QnrB 是一种新型 DnaA 结合蛋白，通过触发 DNA 复制应激来增加细菌突变率
DOI：
10.1111/mmi.14235
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发表时间：
2019-06-01
影响因子：
3.6
通讯作者：
Mi, Kaixia
中科院分区：
文献类型：
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作者：
Li, Xiaojing;Zhang, Yujiao;Mi, Kaixia
细菌抗生素耐药性是由质粒转移或基因突变引起的，是全球性的健康威胁。喹诺酮类抗生素是重要的抗生素，部分原因是它们是完全合成的，并且自然界中不太可能存在耐药基因;尽管如此，喹诺酮类耐药蛋白已经被发现。质粒携带的喹诺酮类耐药蛋白促进喹诺酮类耐药突变体选择的机制尚不清楚。在这里，我们表明QnrB增加了细菌突变率。转录组学和基因组测序分析表明，QnrB促进基因丰度附近的复制起点（oriC）。此外，QnrB的表达水平与复制起点到末端（oriC/ter）的比例，表明QnrB诱导的DNA复制应激。我们的研究结果还表明，QnrB是一种DNA结合蛋白，可能作为DNA复制起始的激活剂。QnrB与DnaA的相互作用促进了DnaA-oriC开放复合物的形成，从而导致DNA复制过度起始。我们的数据表明，质粒携带的QnrB增加细菌突变率和遗传变化可以减轻健身成本所施加的传输质粒。衍生突变可能会损害抗生素的疗效，并威胁到抗生素治疗的价值。加强对细菌如何适应抗生素环境的理解将导致对抗生素耐药感染的新治疗策略。
Bacterial antibiotic resistance, a global health threat, is caused by plasmid transfer or genetic mutations. Quinolones are important antibiotics, partially because they are fully synthetic and resistance genes are unlikely to exist in nature; nonetheless, quinolone resistance proteins have been identified. The mechanism by which plasmid-borne quinolone resistance proteins promotes the selection of quinolone-resistant mutants is unclear. Here, we show that QnrB increases the bacterial mutation rate. Transcriptomic and genome sequencing analyses showed that QnrB promoted gene abundance near the origin of replication (oriC). In addition, the QnrB expression level correlated with the replication origin to terminus (oriC/ter) ratio, indicating QnrB-induced DNA replication stress. Our results also show that QnrB is a DnaA-binding protein that may act as an activator of DNA replication initiation. Interaction of QnrB with DnaA promoted the formation of the DnaA-oriC open complex, which leads to DNA replication over-initiation. Our data indicate that plasmid-borne QnrB increases bacterial mutation rates and that genetic changes can alleviate the fitness cost imposed by transmitted plasmids. Derivative mutations may impair antibiotic efficacy and threaten the value of antibiotic treatments. Enhanced understanding of how bacteria adapt to the antibiotic environment will lead to new therapeutic strategies for antibiotic-resistant infections.