Small Molecule Inhibitors of the Response Regulator ArsR Exhibit Bactericidal Activity against Helicobacter pylori
Small Molecule Inhibitors of the Response Regulator ArsR Exhibit Bactericidal Activity against Helicobacter pylori
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DOI：
10.3390/microorganisms8040503
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发表时间：
2020-04-01
期刊：
影响因子：
4.5
通讯作者：
Lanas, Angel
中科院分区：
文献类型：
--
作者：
Gonzalez, Andres;Casado, Javier;Lanas, Angel
幽门螺杆菌被认为是人类最常见的细菌病原体。由于传统标准疗法的根除率显着降低，这种微生物不断增强的抗生素耐药性已在全世界敲响了警钟。这场抗生素耐药性危机的一个主要挑战是确定新的微生物靶标，其抑制剂可以克服目前流行的耐药组。在本研究中，我们验证了基本反应调节因子 ArsR 作为一种新颖且有前景的幽门螺杆菌感染治疗靶点的用途。使用基于荧光的热位移测定对再利用化学文库进行高通量筛选，鉴定出几种 ArsR 结合物。这些低分子量化合物中至少有四种显着抑制 ArsR 的 DNA 结合活性，并对幽门螺杆菌的抗生素耐药菌株表现出杀菌作用。在ArsR抑制剂中，人次级胆汁酸石胆酸可快速破坏幽门螺杆菌细胞，并与克拉霉素或左氧氟沙星联合使用时表现出部分协同作用，而该化合物对正常人类微生物群代表性成员（如大肠杆菌和表皮葡萄球菌）的抗菌作用似乎无关紧要。我们的研究结果增强了针对由多重耐药性幽门螺杆菌菌株引起的难治性感染的一系列新型治疗工具。
Helicobacter pylori is considered the most prevalent bacterial pathogen in humans. The increasing antibiotic resistance evolved by this microorganism has raised alarm bells worldwide due to the significant reduction in the eradication rates of traditional standard therapies. A major challenge in this antibiotic resistance crisis is the identification of novel microbial targets whose inhibitors can overcome the currently circulating resistome. In the present study, we have validated the use of the essential response regulator ArsR as a novel and promising therapeutic target against H. pylori infections. A high-throughput screening of a repurposing chemical library using a fluorescence-based thermal shift assay identified several ArsR binders. At least four of these low-molecular weight compounds noticeably inhibited the DNA binding activity of ArsR and showed bactericidal effects against antibiotic-resistant strains of H. pylori. Among the ArsR inhibitors, a human secondary bile acid, lithocholic acid, quickly destroyed H. pylori cells and exhibited partial synergistic action in combination with clarithromycin or levofloxacin, while the antimicrobial effect of this compound against representative members of the normal human microbiota such as Escherichia coli and Staphylococcus epidermidis appeared irrelevant. Our results enhance the battery of novel therapeutic tools against refractory infections caused by multidrug-resistant H. pylori strains.