Kolarič Anja, Kokot Maja, Hrast Martina, Weiss Matjaž, Zdovc Irena, Trontelj Jurij, Žakelj Simon, Anderluh Marko, Minovski Nikola
Laboratory for Cheminformatics, Theory Department, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, SI-1000 Ljubljana, Slovenia.
Antibiotics (Basel). 2021 Jul 15;10(7):862. doi: 10.3390/antibiotics10070862.
Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against some of the most concerning hard-to-treat pathogens for which new antibacterials are urgently needed, as reported by the WHO and CDC. NBTIs enzyme activity and whole cell potency seems to depend on the fine-tuned lipophilicity/hydrophilicity ratio that governs the permeability of those compounds through the bacterial membranes. Lipophilicity of NBTIs is apparently optimal for passing through the membrane of Gram-positive bacteria, but the higher, although not excessive lipophilicity and suitable hydrophilicity seems to determine the passage through Gram-negative bacterial membranes. However, due to the considerable hERG inhibition, which is still at least two orders of magnitude away from MICs, continued optimization is required to realize their full potential.
在此，我们报告了一种基于创新的主要为单环右侧片段设计的新型细菌拓扑异构酶抑制剂（NBTIs）聚焦文库，这些片段对DNA促旋酶和拓扑异构酶IV具有活性。它们表现出非常强大且广泛的抗菌活性，甚至对世界卫生组织（WHO）和美国疾病控制与预防中心（CDC）报告的一些最令人担忧的难以治疗的病原体也有活性，而针对这些病原体迫切需要新型抗菌药物。NBTIs的酶活性和全细胞效力似乎取决于微调的亲脂性/亲水性比率，该比率控制着这些化合物通过细菌膜的通透性。NBTIs的亲脂性显然最适合穿过革兰氏阳性菌的膜，但较高（尽管不过度）的亲脂性和合适的亲水性似乎决定了其穿过革兰氏阴性菌膜的情况。然而，由于存在相当程度的人醚 - 去极化钾通道（hERG）抑制作用，尽管其与最低抑菌浓度（MICs）仍至少相差两个数量级，但仍需要持续优化以充分发挥其潜力。
