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Lipophosphonoxins II: Design, Synthesis, and Properties of Novel Broad Spectrum Antibacterial Agents
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-12 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00355 Gabriela Seydlová 1 , Radek Pohl 2 , Eva Zborníková 2, 3 , Marcel Ehn 2 , Ondřej Šimák 2 , Natalya Panova 4 , Milan Kolář 5 , Kateřina Bogdanová 5 , Renata Večeřová 5 , Radovan Fišer 1 , Hana Šanderová 4 , Dragana Vítovská 4 , Petra Sudzinová 1, 4 , Jiří Pospíšil 1, 4 , Oldřich Benada 4 , Tomáš Křížek 3 , David Sedlák 6 , Petr Bartůněk 6 , Libor Krásný 4 , Dominik Rejman 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-12 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00355 Gabriela Seydlová 1 , Radek Pohl 2 , Eva Zborníková 2, 3 , Marcel Ehn 2 , Ondřej Šimák 2 , Natalya Panova 4 , Milan Kolář 5 , Kateřina Bogdanová 5 , Renata Večeřová 5 , Radovan Fišer 1 , Hana Šanderová 4 , Dragana Vítovská 4 , Petra Sudzinová 1, 4 , Jiří Pospíšil 1, 4 , Oldřich Benada 4 , Tomáš Křížek 3 , David Sedlák 6 , Petr Bartůněk 6 , Libor Krásný 4 , Dominik Rejman 2
Affiliation
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The increase in the number of bacterial strains resistant to known antibiotics is alarming. In this study we report the synthesis of novel compounds termed Lipophosphonoxins II (LPPO II). We show that LPPO II display excellent activities against Gram-positive and -negative bacteria, including pathogens and multiresistant strains. We describe their mechanism of action–plasmatic membrane pore-forming activity selective for bacteria. Importantly, LPPO II neither damage nor cross the eukaryotic plasmatic membrane at their bactericidal concentrations. Further, we demonstrate LPPO II have low propensity for resistance development, likely due to their rapid membrane-targeting mode of action. Finally, we reveal that LPPO II are not toxic to either eukaryotic cells or model animals when administered orally or topically. Collectively, these results suggest that LPPO II are highly promising compounds for development into pharmaceuticals.
中文翻译：
Lipophosphonoxins II：新型广谱抗菌剂的设计，合成和性质
对已知抗生素具有抗性的细菌菌株数量的增加令人震惊。在这项研究中，我们报告了称为Lipophosphonoxins II（LPPO II）的新型化合物的合成。我们表明，LPPO II对革兰氏阳性和阴性细菌，包括病原体和多药耐药菌株显示出出色的活动。我们描述了它们的作用机理-对细菌具有选择性的质膜孔形成活性。重要的是，LPPO II在其杀菌浓度下既不会损坏也不会穿过真核质膜。此外，我们证明了LPPO II具有较低的耐药性发展倾向，这可能是由于其快速的膜靶向作用模式所致。最后，我们揭示了口服或局部给药时，LPPO II对真核细胞或模型动物均无毒。总的来说，
更新日期：2017-07-13
中文翻译：
Lipophosphonoxins II：新型广谱抗菌剂的设计，合成和性质
对已知抗生素具有抗性的细菌菌株数量的增加令人震惊。在这项研究中，我们报告了称为Lipophosphonoxins II（LPPO II）的新型化合物的合成。我们表明，LPPO II对革兰氏阳性和阴性细菌，包括病原体和多药耐药菌株显示出出色的活动。我们描述了它们的作用机理-对细菌具有选择性的质膜孔形成活性。重要的是，LPPO II在其杀菌浓度下既不会损坏也不会穿过真核质膜。此外，我们证明了LPPO II具有较低的耐药性发展倾向，这可能是由于其快速的膜靶向作用模式所致。最后，我们揭示了口服或局部给药时，LPPO II对真核细胞或模型动物均无毒。总的来说，
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