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Dual Escherichia coli DNA Gyrase A and B Inhibitors with Antibacterial Activity.
ChemMedChem ( IF 3.6 ) Pub Date : 2019-12-10 , DOI: 10.1002/cmdc.201900607 Benedetta Fois 1, 2 , Žiga Skok 1 , Tihomir Tomašič 1 , Janez Ilaš 1 , Nace Zidar 1 , Anamarija Zega 1 , Lucija Peterlin Mašič 1 , Petra Szili 3, 4 , Gábor Draskovits 3 , Ákos Nyerges 3 , Csaba Pál 3 , Danijel Kikelj 1
ChemMedChem ( IF 3.6 ) Pub Date : 2019-12-10 , DOI: 10.1002/cmdc.201900607 Benedetta Fois 1, 2 , Žiga Skok 1 , Tihomir Tomašič 1 , Janez Ilaš 1 , Nace Zidar 1 , Anamarija Zega 1 , Lucija Peterlin Mašič 1 , Petra Szili 3, 4 , Gábor Draskovits 3 , Ákos Nyerges 3 , Csaba Pál 3 , Danijel Kikelj 1
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The emergence of multidrug-resistant bacteria is a global health threat necessitating the discovery of new antibacterials and novel strategies for fighting bacterial infections. We report first-in-class DNA gyrase B (GyrB) inhibitor/ciprofloxacin hybrids that display antibacterial activity against Escherichia coli. Whereas DNA gyrase ATPase inhibition experiments, DNA gyrase supercoiling assays, and in vitro antibacterial assays suggest binding of the hybrids to the E. coli GyrA and GyrB subunits, an interaction with the GyrA fluoroquinolone-binding site seems to be solely responsible for their antibacterial activity. Our results provide a foundation for a new concept of facilitating entry of nonpermeating GyrB inhibitors into bacteria by conjugation with ciprofloxacin, a highly permeable GyrA inhibitor. A hybrid molecule containing GyrA and GyrB inhibitor parts entering the bacterial cell would then elicit a strong antibacterial effect by inhibition of both the GyrA and GyrB subunits of DNA gyrase and potentially slow bacterial resistance development.
中文翻译：
具有抗菌活性的双重大肠杆菌DNA促旋酶A和B抑制剂。
耐多药细菌的出现是对全球健康的威胁，因此有必要发现新的抗菌素和与细菌感染作斗争的新策略。我们报告一流的DNA回旋酶B（GyrB）抑制剂/环丙沙星杂种，对大肠杆菌表现出抗菌活性。尽管DNA旋转酶ATPase抑制实验，DNA旋转酶超螺旋测定和体外抗菌测定表明杂合体与大肠杆菌GyrA和GyrB亚基结合，但与GyrA氟喹诺酮结合位点的相互作用似乎是其抗菌活性的唯一原因。我们的研究结果为通过与高渗透性GyrA抑制剂环丙沙星结合促进非渗透性GyrB抑制剂进入细菌的新概念奠定了基础。
更新日期：2019-12-11
中文翻译：
具有抗菌活性的双重大肠杆菌DNA促旋酶A和B抑制剂。
耐多药细菌的出现是对全球健康的威胁，因此有必要发现新的抗菌素和与细菌感染作斗争的新策略。我们报告一流的DNA回旋酶B（GyrB）抑制剂/环丙沙星杂种，对大肠杆菌表现出抗菌活性。尽管DNA旋转酶ATPase抑制实验，DNA旋转酶超螺旋测定和体外抗菌测定表明杂合体与大肠杆菌GyrA和GyrB亚基结合，但与GyrA氟喹诺酮结合位点的相互作用似乎是其抗菌活性的唯一原因。我们的研究结果为通过与高渗透性GyrA抑制剂环丙沙星结合促进非渗透性GyrB抑制剂进入细菌的新概念奠定了基础。
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