Ramić Alma, Skočibušić Mirjana, Odžak Renata, Čipak Gašparović Ana, Milković Lidija, Mikelić Ana, Sović Karlo, Primožič Ines, Hrenar Tomica
Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia.
Faculty of Science, University of Split, 21000 Split, Croatia.
Antibiotics (Basel). 2021 May 31;10(6):659. doi: 10.3390/antibiotics10060659.
Bacterial infections that do not respond to current treatments are increasing, thus there is a need for the development of new antibiotics. Series of 20 -substituted quaternary salts of cinchonidine (CD) and their quasi-enantiomer cinchonine (CN) were prepared and their antimicrobial activity was assessed against a diverse panel of Gram-positive and Gram-negative bacteria. All tested compounds showed good antimicrobial potential (minimum inhibitory concentration (MIC) values 1.56 to 125.00 μg/mL), proved to be nontoxic to different human cell lines, and did not influence the production of reactive oxygen species (ROS). Seven compounds showed very strong bioactivity against some of the tested Gram-negative bacteria (MIC for and 6.25 μg/mL; MIC for 1.56 μg/mL). To establish a connection between antimicrobial data and potential energy surfaces (PES) of the compounds, activity/PES models using principal components of the disc diffusion assay and MIC and data towards PES data were built. An extensive machine learning procedure for the generation and cross-validation of multivariate linear regression models with a linear combination of original variables as well as their higher-order polynomial terms was performed. The best possible models with predicted (CD derivatives) = 0.9979 and (CN derivatives) = 0.9873 were established and presented. This activity/PES model can be used for accurate prediction of activities for new compounds based solely on their potential energy surfaces, which will enable wider screening and guided search for new potential leads. Based on the obtained results, -quaternary derivatives of alkaloids proved to be an excellent scaffold for further optimization of novel antibiotic species.
对当前治疗无反应的细菌感染正在增加，因此需要开发新的抗生素。制备了一系列20-取代的辛可尼定（CD）季铵盐及其准对映体辛可宁（CN），并评估了它们对多种革兰氏阳性和革兰氏阴性细菌的抗菌活性。所有测试化合物均显示出良好的抗菌潜力（最低抑菌浓度（MIC）值为1.56至125.00μg/mL），对不同人类细胞系无毒，且不影响活性氧（ROS）的产生。七种化合物对一些测试的革兰氏阴性细菌表现出非常强的生物活性（对大肠杆菌和肺炎克雷伯菌的MIC为6.25μg/mL；对铜绿假单胞菌的MIC为1.56μg/mL）。为了建立化合物的抗菌数据与势能面（PES）之间的联系，构建了使用纸片扩散试验主成分以及MIC和PES数据的活性/PES模型。对具有原始变量及其高阶多项式项线性组合的多元线性回归模型进行了广泛的机器学习生成和交叉验证过程。建立并展示了预测值（CD衍生物）=0.9979和（CN衍生物）=0.9873的最佳可能模型。这种活性/PES模型可用于仅基于新化合物的势能面准确预测其活性，这将有助于更广泛地筛选和有针对性地寻找新的潜在先导化合物。基于所得结果，生物碱的 - 季铵衍生物被证明是进一步优化新型抗生素种类的优良骨架。
