作为 NorA 外排泵抑制剂,梅尔德隆酸衍生化合物对金黄色葡萄球菌菌株的体外和硅学效应。

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biophysical chemistry Pub Date : 2024-10-18 DOI:10.1016/j.bpc.2024.107344
Isaac Moura Araújo , Raimundo Luiz Silva Pereira , Ana Carolina Justino de Araújo , Sheila Alves Gonçalves , Saulo Relison Tintino , Cícera Datiane de Morais Oliveira-Tintino , Irwin Rose Alencar de Menezes , Renata Salamoni , Iêda Maria Begnini , Ricardo Andrade Rebelo , Luiz Everson da Silva , Carolina Bandeira Domiciano , Henrique Douglas Melo Coutinho
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引用次数: 0

摘要

抗生素的滥用导致对这些药物产生抗药性的细菌菌株数量惊人地增加。将抗生素排出细菌细胞的外排泵已成为细菌产生耐药性的关键机制之一。为了消除和减轻细菌的耐药性,研究人员将目光转向了外排泵抑制剂,将其作为一种潜在的解决方案。梅尔杜姆酸是一种广泛用于合成生物活性化合物的合成分子,在这方面引起了极大的兴趣。因此,本研究采用了硅学和体外方法,旨在研究美杜莎酸的三种衍生物的抗菌活性,并评估其在抑制外流机制方面的功效。衍生物的抗菌活性是通过严格的肉汤微稀释试验进行评估的。虽然这些衍生物本身没有表现出直接的抗菌活性,但它们在增强抗生素效果方面表现出了显著的潜力。此外,使用溴化乙锭(EtBr)进行的荧光发射测定显示,其荧光水平与阳性对照相当,这表明它们可能阻断了外排泵。在硅学中进行的分子对接研究进一步证实了这些发现,研究显示了与诺氟沙星和CCCP(已知的外排泵抑制剂)类似的结合相互作用。这些结果凸显了美杜莎酸衍生物作为有效外排泵抑制剂的潜力。通过抑制这些机制,这些衍生物有望提高抗生素的疗效并对抗细菌耐药性。这项研究为开发解决细菌耐药性这一紧迫问题的新策略提供了宝贵的见解,并为这一领域的进一步研究和探索铺平了道路。
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In vitro and in silico effect of meldrum's acid-derived compounds on Staphylococcus aureus strains as NorA efflux pump inhibitors
The misuse of antibiotics has led to an alarming increase in bacterial strains resistant to these drugs. Efflux pumps, which expel antibiotics from bacterial cells, have emerged as one of the key mechanisms of bacterial resistance. In the quest to combat and mitigate bacterial resistance, researchers have turned their attention to efflux pump inhibitors as a potential solution. Meldrum's acid, a synthetic molecule widely utilized in the synthesis of bioactive compounds, has garnered significant interest in this regard. Hence, this study aims to investigate the antibacterial activity and evaluate the efficacy of three derivatives of meldrum's acid in inhibiting efflux mechanisms, employing both in silico and in vitro approaches. The antibacterial activity of the derivatives was assessed through rigorous broth microdilution testing. While the derivatives themselves did not exhibit direct antibacterial activity, they demonstrated remarkable potential in potentiating the effects of antibiotics. Additionally, fluorescence emission assays using ethidium bromide (EtBr) revealed fluorescence levels comparable to the positive control, indicating a possible blockade of efflux pumps. Molecular docking studies conducted in silico further supported these findings by revealing binding interactions similar to norfloxacin and CCCP, known efflux pump inhibitors. These results underscore the potential of meldrum's acid derivatives as effective inhibitors of efflux pumps. By inhibiting these mechanisms, the derivatives hold promise in enhancing the effectiveness of antibiotics and combatting bacterial resistance. This study contributes valuable insights into the development of novel strategies to address the pressing issue of bacterial resistance and paves the way for further research and exploration in this field.
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来源期刊
Biophysical chemistry
Biophysical chemistry 生物-生化与分子生物学
CiteScore
6.10
自引率
10.50%
发文量
121
审稿时长
20 days
期刊介绍: Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.
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