Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli
Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli
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DOI：
10.1371/journal.pone.0178303
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发表时间：
2017-05-22
期刊：
影响因子：
3.7
通讯作者：
Crane, John K.
中科院分区：
文献类型：
--
作者：
Bunnell, Bryan E.;Escobar, Jillian F.;Crane, John K.
锌通过诱导包膜应激反应和抑制SOS反应抑制致泻性大肠杆菌的毒力。SOS反应是由细菌DNA的损伤触发的。在志贺产毒大肠杆菌中，SOS反应强烈诱导志贺毒素(STX)和编码STX基因的噬菌体的产生。在大肠杆菌中，SOS反应的诱导伴随着更高的突变率，称为突变子反应，这是由于当DNA损伤太严重而不能用规范的DNA聚合酶修复时，容易出错的DNA聚合酶引起的。由于锌抑制了SOS反应的其他方面，我们假设锌也会抑制突变反应，也就是众所周知的超突变。我们探索了各种不同的实验范式来诱导由SOS反应触发的超突变，发现超突变不仅被经典的诱导剂如丝裂霉素C和喹诺酮类抗生素所诱导，还被抗病毒药物如齐多夫定和抗癌药物如5-氟尿嘧啶、6-巯基嘌呤和氮胞苷所诱导。锌盐对大肠杆菌和肺炎克雷伯菌的SOS反应和超突变现象均有抑制作用，且锌盐对SOS反应的抑制作用比其他金属更强。然后，我们试图确定锌在培养液中外部施加，抑制超突变的机制。我们的结果表明，锌干扰了RecA的活动，并保护LexA免受RecA介导的切割，这是启动SOS反应的早期步骤。SOS反应可能在抗生素耐药性的形成中发挥作用，锌的作用提示了预防它的方法。
Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx) and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.