Department of Botany, Meerut College, Meerut, 250003 (U.P.), India.
Chemistry Section, Pharmacopoeia Commission for Indian Medicine, and Homoeopathy (PCIM&H), Ministry of Ayush, Ghaziabad, 201002, (U.P.), India.
Med Chem. 2024;20(6):557-575. doi: 10.2174/0115734064263586231022135644.
Antimicrobial resistance development poses a significant danger to the efficacy of antibiotics, which were once believed to be the most efficient method for treating infections caused by bacteria. Antimicrobial resistance typically involves various mechanisms, such as drug inactivation or modification, drug target modification, drug uptake restriction, and drug efflux, resulting in decreased antibiotic concentrations within the cell. Antimicrobial resistance has been associated with efflux Pumps, known for their capacity to expel different antibiotics from the cell non-specifically. This makes EPs fascinating targets for creating drugs to combat antimicrobial resistance (AMR). The varied structures of secondary metabolites (phytomolecules) found in plants have positioned them as a promising reservoir of efflux pump inhibitors. These inhibitors act as modifiers of bacterial resistance and facilitate the reintroduction of antibiotics that have lost clinical effectiveness. Additionally, they may play a role in preventing the emergence of multidrug resistant strains.
The objective of this review article is to discuss the latest studies on plant-based efflux pump inhibitors such as terpenoids, alkaloids, flavonoids, glycosides, and tetralones. It highlighted their potential in enhancing the effectiveness of antibiotics and combating the development of multidrug resistance.
Efflux pump inhibitors (EPIs) derived from botanical sources, including compounds like lysergol, chanaoclavine, niazrin, 4-hydroxy-α-tetralone, ursolic acid, phytol, etc., as well as their partially synthesized forms, have shown significant potential as practical therapeutic approaches in addressing antimicrobial resistance caused by efflux pumps. Further, several phyto-molecules and their analogs demonstrated superior potential for reversing drug resistance, surpassing established agents like reserpine, niaziridin, etc. Conclusion: This review found that while the phyto-molecules and their derivatives did not possess notable antimicrobial activity, their combination with established antibiotics significantly reduced their minimum inhibitory concentration (MIC). Specific molecules, such as chanaoclavine and niaziridin, exhibited noteworthy potential in reversing the effectiveness of drugs, resulting in a reduction of the MIC of tetracycline by up to 16 times against the tested strain of bacteria. These molecules inhibited the efflux pumps responsible for drug resistance and displayed a stronger affinity for membrane proteins. By employing powerful EPIs, these molecules can selectively target and obstruct drug efflux pumps. This targeted approach can significantly augment the strength and efficacy of older antibiotics against various drug resistant bacteria, given that active drug efflux poses a susceptibility for nearly all antibiotics.
抗生素耐药性的发展对抗生素的疗效构成了重大威胁，而抗生素曾被认为是治疗细菌感染最有效的方法。抗生素耐药性通常涉及多种机制，例如药物失活或修饰、药物靶标修饰、药物摄取限制和药物外排，导致细胞内抗生素浓度降低。抗生素耐药性与外排泵有关，外排泵以非特异性地将不同的抗生素从细胞中排出而闻名。这使得外排泵成为开发抗抗生素耐药性（AMR）药物的有趣靶点。植物中发现的次级代谢产物（植物分子）的结构多样，使它们成为外排泵抑制剂的有前途的来源。这些抑制剂作为细菌耐药性的调节剂，促进了失去临床效果的抗生素的重新引入。此外，它们还可能在防止多药耐药株的出现方面发挥作用。
本文综述了植物源性外排泵抑制剂的最新研究进展，如萜类、生物碱、类黄酮、糖苷和四氢酮等。它强调了它们在增强抗生素有效性和对抗多药耐药性发展方面的潜力。
从植物中提取的外排泵抑制剂（EPIs），包括麦角酰二乙胺、金雀花碱、尼扎林、4-羟基-α-四氢酮、熊果酸、叶绿醇等化合物及其部分合成形式，作为解决由外排泵引起的抗生素耐药性的实用治疗方法具有很大的潜力。此外，几种植物分子及其类似物表现出逆转耐药性的卓越潜力，超过了利血平、尼扎林等现有药物。
综述发现，虽然植物分子及其衍生物本身没有显著的抗菌活性，但与现有抗生素联合使用可显著降低其最小抑菌浓度（MIC）。特定分子，如金雀花碱和尼扎林，在逆转药物效果方面表现出显著的潜力，可使四环素对测试细菌菌株的 MIC 降低高达 16 倍。这些分子抑制了导致耐药性的外排泵，并显示出对膜蛋白更强的亲和力。通过使用强大的 EPIs，这些分子可以选择性地针对并阻断药物外排泵。这种靶向方法可以显著增强针对各种耐药细菌的旧抗生素的强度和功效，因为主动药物外排几乎对所有抗生素都具有易感性。
