Inhibition of mutation and combating the evolution of antibiotic resistance
Inhibition of mutation and combating the evolution of antibiotic resistance
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DOI：
10.1371/journal.pbio.0030176
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发表时间：
2005-06-01
期刊：
影响因子：
9.8
通讯作者：
Romesberg, FE
中科院分区：
文献类型：
--
作者：
Cirz, RT;Chin, JK;Romesberg, FE
耐药菌的出现对人类健康构成严重威胁。在几种抗生素的情况下，包括喹诺酮和利福霉素类的抗生素，细菌在治疗期间通过染色体基因突变迅速获得耐药性。在这项工作中，我们表明，通过干扰蛋白酶莱克萨的活性，防止诱导SOS反应，使致病性大肠杆菌无法在体内发展耐药性环丙沙星或利福平，重要的喹诺酮类和利福霉素抗生素。我们在体外表明，在RecBC介导的环丙沙星介导的DNA损伤的修复过程中诱导莱克萨裂解，这导致SOS调节的聚合酶Pol II，Pol IV和Pol V的去阻遏，它们合作诱导耐药突变。我们的研究结果表明，抑制突变可以作为一种新的治疗策略，以打击抗生素耐药性的演变。
The emergence of drug-resistant bacteria poses a serious threat to human health. In the case of several antibiotics, including those of the quinolone and rifamycin classes, bacteria rapidly acquire resistance through mutation of chromosomal genes during therapy. In this work, we show that preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic Escherichia coli unable to evolve resistance in vivo to ciprofloxacin or rifampicin, important quinolone and rifamycin antibiotics. We show in vitro that LexA cleavage is induced during RecBC-mediated repair of ciprofloxacin-mediated DNA damage and that this results in the derepression of the SOS-regulated polymerases Pol II, Pol IV and Pol V, which collaborate to induce resistance-conferring mutations. Our findings indicate that the inhibition of mutation could serve as a novel therapeutic strategy to combat the evolution of antibiotic resistance.