针对耐多药细菌菌株的克林霉素衍生物的设计、合成和生物活性评估

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-05-05 DOI:10.1002/ddr.22182
Yiduo Jia, Yinmeng Zhang, Hong Zhu, Ming Wang
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引用次数: 0

摘要

我们的研究旨在降低克林霉素对革兰氏阳性菌的细菌耐药性,并扩大其细菌药敏范围。首先,我们根据克林霉素的结构-活性关系优化了其结构。其次,我们采用分数抑制浓度法检测适合与克林霉素衍生物联用的药物。然后,我们使用连接剂将克林霉素衍生物与确定的联合治疗药物连接起来。最后,我们进行了抗菌药敏试验和体外细菌抑制活性测定,以确定疗效最高的化合物。研究结果表明,我们合成了克林霉素丙酸酯衍生物和克林霉素同/异二聚体衍生物,与克林霉素和其他抗生素相比,它们对细菌和真菌都具有更强的抗菌活性。针对四种革兰氏阴性菌和一种真菌的体外抑菌活性测试表明,所有合成化合物的抑菌效果至少是克林霉素和磺胺类药物的 1000 倍。这些化合物的最低抑菌浓度(MIC)值在 0.25 至 0.0325 mM 之间。值得注意的是,化合物 5a 对三种不同细菌菌株的抑制活性最强,MIC 值从 0.0625 毫摩尔到 0.0325 毫摩尔不等。此外,我们的计算表明,化合物 5a 在细胞中的使用是安全的。总之,合成的化合物在解决细菌抗生素耐药性问题上大有可为。
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Design, synthesis, and bioactivity evaluation of clindamycin derivatives against multidrug-resistant bacterial strains

Our research aims to reduce the bacterial resistance of clindamycin against Gram-positive bacteria and expand its range of bacterial susceptibility. First, we optimized the structure of clindamycin based on its structure–activity relationship. Second, we employed the fractional inhibitory concentration method to detect drugs suitable for combination with clindamycin derivatives. We then used a linker to connect the clindamycin derivatives with the identified combined therapy drugs. Finally, we tested antibacterial susceptibility testing and conducted in vitro bacterial inhibition activity assays to determine the compounds. with the highest efficacy. The results of our study show that we synthesized clindamycin propionate derivatives and clindamycin homo/heterodimer derivatives, which exhibited superior antibacterial activity compared to clindamycin and other antibiotics against both bacteria and fungi. In vitro bacteriostatic activity testing against four types of Gram-negative bacteria and one type of fungi revealed that all synthesized compounds had bacteriostatic effects at least 1000 times better than clindamycin and sulfonamides. The minimum inhibitory concentration (MIC) values for these compounds ranged from 0.25 to 0.0325 mM. Significantly, compound 5a demonstrated the most potent inhibitory activity against three distinct bacterial strains, displaying MIC values spanning from 0.0625 to 0.0325 mM. Furthermore, our calculations indicate that compound 5a is safe for cellular use. In conclusion, the synthesized compounds hold great promise in addressing bacterial antibiotic resistance.

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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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