From Phenylthiazoles to Phenylpyrazoles: Broadening the Antibacterial Spectrum toward Carbapenem-Resistant Bacteria
From Phenylthiazoles to Phenylpyrazoles: Broadening the Antibacterial Spectrum toward Carbapenem-Resistant Bacteria
复制标题
DOI：
10.1021/acs.jmedchem.9b00720
复制
发表时间：
2019-09-12
影响因子：
7.3
通讯作者：
Mayhoub, Abdelrahman S.
中科院分区：
文献类型：
--
作者：
Hammad, Ali;Abutaleb, Nader S.;Mayhoub, Abdelrahman S.
通过用吡唑环取代中心噻唑，同时保持其其他药效学特征，扩大了苯基噻唑类抗生素的狭窄抗菌谱。最有前途的衍生物，化合物23，是更有效的万古霉素对多重耐药革兰氏阳性临床分离株，包括万古霉素和利奈唑胺耐药耐甲氧西林金黄色葡萄球菌（MRSA），最低抑菌浓度（MIC）值低至0.5 μ g/mL。此外，化合物23上级亚胺培南和美罗培南对高致病性碳青霉烯类耐药菌株，如鲍曼不动杆菌，肺炎克雷伯菌和大肠杆菌。除了显著的生物膜抑制活性之外，化合物23在降低革兰氏阳性和革兰氏阴性病原菌的细胞内负荷方面优于万古霉素和卡那霉素。化合物23在2X MIC下清除90%的细胞内MRSA和98%的沙门氏菌。此外，初步的药代动力学研究表明，这类新型抗菌化合物具有高度代谢稳定性，生物半衰期为10.5小时，表明每日一次给药方案。
The narrow antibacterial spectrum of phenylthiazole antibiotics was expanded by replacing central thiazole with a pyrazole ring while maintaining its other pharmacophoric features. The most promising derivative, compound 23, was more potent than vancomycin against multidrug-resistant Gram-positive clinical isolates, including vancomycin- and linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) value as low as 0.5 mu g/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. In addition to the notable biofilm inhibition activity, compound 23 outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound 23 cleared 90% of intracellular MRSA and 98% of Salmonella enteritidis at 2X the MIC. Moreover, preliminary pharmacokinetic investigations indicated that this class of novel antibacterial compounds is highly metabolically stable with a biological half-life of 10.5 h, suggesting a once-daily dosing regimen.