The evolution of antibiotic resistance
The evolution of antibiotic resistance
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DOI：
10.1096/fasebj.21.5.a94-b
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发表时间：
2007-04
期刊：
影响因子：
--
通讯作者：
Floyd Romesberg
中科院分区：
文献类型：
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作者：
Floyd Romesberg
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，包括氟喹诺酮和利福霉素类的抗生素，细菌在治疗期间从染色体基因突变中迅速获得耐药性。我们最近发现，通过干扰蛋白酶莱克萨的活性来阻止SOS反应的诱导，使致病性E.大肠杆菌不能在体内对环丙沙星或利福平、原型喹诺酮和利福霉素抗生素产生耐药性。我们在体外证明，在RecBC介导的环丙沙星介导的DNA损伤修复过程中诱导了莱克萨裂解，这导致SOS调节的聚合酶Pol II、Pol IV和Pol V的去抑制，这些聚合酶共同诱导了耐药突变。我们还表明，这些聚合酶的去抑制是错配修复缺陷细胞中超突变所必需的。铜绿假单胞菌和S. aureus也在进行中，将检查这些结果的一般性。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 fluoroquinolone and rifamycin classes, bacteria rapidly acquire resistance from mutation of chromosomal genes during therapy. We have recently shown that preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic E. coli unable to evolve resistance in vivo to ciprofloxacin or rifampicin, the prototypical 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 de‐repression of the SOS‐regulated polymerases, Pol II, Pol IV, and Pol V, which collaborate to induce resistance‐conferring mutations. We have also shown that de‐repression of these polymerases is required for hypermutation in mismatch repair‐defective cells. Initial studies with P. aeruginosa and S. aureus are also underway which will examine the generality of these results. Our findings indicate that the inhibition of mutation could serve as a novel therapeutic strategy to combat the evolution of antibiotic resistance.