Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase
Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase
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DOI：
10.1073/pnas.1700721114
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发表时间：
2017-05-30
影响因子：
11.1
通讯作者：
Stavenger, Robert A.
中科院分区：
文献类型：
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作者：
Chan, Pan F.;Germe, Thomas;Stavenger, Robert A.
目前正在开发的新型有效抗菌药正在开发中，以治疗抗菌素耐药性的日益增长的威胁，特别是在革兰氏阴性医院病原体中，这导致了抗生素药物发现的新努力。氟喹诺酮类药物是一种广谱抗菌药，通过稳定DNA裂解复合体来靶向DNA旋转酶，但其临床应用受到耐药性的影响。我们已经确定了一类以DNA旋转酶为靶点的抗菌噻吩类化合物，具有独特的作用机制，并对一系列细菌病原体具有活性，包括对氟喹诺酮类药物耐药的菌株。虽然氟喹诺酮类药物能稳定双链DNA断裂，但抗菌的噻吩类药物能稳定旋转酶介导的DNA裂解复合体在一条DNA链或两条DNA链上。DNA旋转酶-DNA复合体的X射线结晶学显示，这些化合物结合在远离DNA的有翼螺旋结构域和拓扑异构酶-底物酶结构域之间的蛋白质口袋上。这个口袋周围的保守残基的突变会影响噻吩类抑制剂的活性，这与DNA旋转酶的变构抑制是一致的。这种可药物口袋为针对抗生素开发的细菌拓扑异构酶提供了潜在的补充机会。
A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase-DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.