Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens
Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens
复制标题
DOI：
10.1021/jm501552x
复制
发表时间：
2014-12-11
影响因子：
7.3
通讯作者：
Tommasi, Ruben
中科院分区：
文献类型：
--
作者：
Brown, Dean G.;May-Dracka, Tricia L.;Tommasi, Ruben
为了更好地理解从企业筛选中鉴定新型抗菌化合物的困难，研究人员分析了3200种抗菌项目中具有抗革兰氏阴性或革兰氏阳性病原体全细胞活性的化合物的物理特性，并将其与在生化和表型细菌靶标上进行的高通量（HTS）筛选中发现的活性进行了比较。23个抗菌HTS筛选的输出表明，与抗菌项目化合物的性能相比，HTS活性明显高于抗菌项目化合物（通常高24个log单位），此外，14/23个HTS筛选的平均clogD高于筛选收集的平均值（筛选收集clogD = 2.45）。人们发现，这样做的后果如下：(a)铅鉴定程序通常进一步获得疏水特性，增加生化效力，使已知抗菌剂的物理化学性质与HTS活性起始点之间的分离更大；(b)血浆蛋白结合和细胞毒性的可能性经常增加；(c)革兰氏阴性菌的细胞活性受到严重限制，或者如果存在，则表现出显著的外排。我们的分析表明，对外排最不敏感的化合物是那些极性高、分子量小或非常大、通常是两性离子的化合物。疏水性通常是HTS活性的主要驱动因素，但往往会阻碍整个细胞的抗菌活性。然而，简单地设计极性化合物是不够的抗菌活性，并指出缺乏对复杂和特定的细菌渗透机制的理解。
To better understand the difficulties surrounding the identification of novel antibacterial compounds from corporate screening collections, physical properties of similar to 3200 antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found from high throughput (HTS) screens conducted on both biochemical and phenotypic bacterial targets. The output from 23 antibacterial HTS screens illustrated that when compared to the properties of the antibacterial project compounds, the HTS actives were significantly more hydrophobic than antibacterial project compounds (typically 24 log units higher), and furthermore, for 14/23 HTS screens, the average clogD was higher than the screening collection average (screening collection clogD = 2.45). It was found that the consequences of this were the following: (a) lead identification programs often further gained hydrophobic character with increased biochemical potency, making the separation even larger between the physicochemical properties of known antibacterial agents and the HTS active starting point, (b) the probability of plasma protein binding and cytotoxicity are often increased, and (c) cell-based activity in Gram-negative bacteria was severely limited or, if present, demonstrated significant efflux. Our analysis illustrated that compounds least susceptible to efflux were those which were highly polar and small in MW or very large and typically zwitterionic. Hydrophobicity was often the dominant driver for HTS actives but, more often than not, precluded whole cell antibacterial activity. However, simply designing polar compounds was not sufficient for antibacterial activity and pointed to a lack of understanding of complex and specific bacterial penetration mechanisms.