Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 3, 21 000, Novi Sad, Vojvodina, Serbia.
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 3, 21 000, Novi Sad, Vojvodina, Serbia.
J Ethnopharmacol. 2021 Jan 10;264:113266. doi: 10.1016/j.jep.2020.113266. Epub 2020 Aug 15.
Bile traditionally was used in wound healing, having erodent, antioxidant and antimicrobial potential. Acinetobacter baumannii is a frequent etiological agent of wound infections, exhibiting high level of resistance to conventional antibiotics.
To determine the effect of selected bile acid sodium salts and their 3-dehydro (i.e. 3-oxo) derivatives, as well as their combinations with commercial antibiotics against A. baumanniia, to confirm bile ethnopharmacological application in wound healing from aspect of microbiology.
The sensitivity of reference and multidrug resistant (MDR) A. baumannii strains to bile salts, their derivatives and conventional antibiotics were examined by a microtiter plate method. The interaction of bile salts/derivatives and antibiotics was examined by a checkerboard method and time kill curve method. The interaction of bile salts with ciprofloxacin in terms of micelles formation was examined by DOSY NMR technique.
The bile salts sodium deoxycholate (Na-DCA) and sodium chenodeoxycholate (Na-CDCA), as well as their derivatives sodium 3-dehydro-deoxycholate (Na-3DH-DCA) and sodium 3-dehydro-chenodeoxycholate (Na-3DH-CDCA), potentiate antibiotic activity and resensitize A. baumannii. The bile salts and their derivatives enhance A. baumannii sensitivity to antibiotics, particularly those that should penetrate cell to exhibit activity. The sodium salts of bile acid derivatives, namely Na-3DH-DCA and Na-3DH-CDCA, showed synergy against both reference and MDR strain in combination with ciprofloxacin or gentamicin, while synergy with gentamicin was obtained in all combinations, regardless of bile salt type and bacterial strains. The synergy with Na-3DH-CDCA was further confirmed by the time-kill curve method, as bacterial number decreased after 12 h. NMR experiment revealed that this bile salt derivative and ciprofloxacin form co-aggregates when bile salts concentration was higher than critical micelle concentrations (CMC), which indicate the possibility that bile salts enhance ciprofloxacin cell penetration by membrane destabilization, contributing to the synergy.
The synergistic interactions between bile salts or derivatives with ciprofloxacin and particularly gentamicin represent a promising strategy for the treatment of A. baumannii wound infections.
传统上，胆汁被用于伤口愈合，具有侵蚀性、抗氧化和抗菌潜力。鲍曼不动杆菌是伤口感染的常见病因，对常规抗生素表现出高水平的耐药性。
确定选定的胆汁酸钠盐及其 3-脱氢（即 3-氧代）衍生物以及它们与商业抗生素组合对鲍曼不动杆菌的影响，从微生物学角度证实胆汁在伤口愈合中的民族药理学应用。
通过微量滴定板法检查参考和多药耐药（MDR）鲍曼不动杆菌菌株对胆汁盐、其衍生物和常规抗生素的敏感性。通过棋盘法和时间杀伤曲线法检查胆汁盐/衍生物和抗生素的相互作用。通过 DOSY NMR 技术检查胆汁盐与环丙沙星在胶束形成方面的相互作用。
胆汁盐脱氧胆酸钠（Na-DCA）和胆酸钠（Na-CDCA）以及它们的衍生物 3-脱氢去氧胆酸钠（Na-3DH-DCA）和 3-脱氢胆酸钠（Na-3DH-CDCA）增强了抗生素的活性并使鲍曼不动杆菌重新敏感。胆汁盐和它们的衍生物增强了鲍曼不动杆菌对抗生素的敏感性，特别是那些应该穿透细胞发挥作用的抗生素。胆汁酸衍生物的钠盐，即 Na-3DH-DCA 和 Na-3DH-CDCA，与环丙沙星或庆大霉素联合使用时对参考和 MDR 菌株均表现出协同作用，而与庆大霉素的协同作用在所有组合中均得到了证实，而与胆汁盐的类型和细菌株无关。通过时间杀伤曲线法进一步证实了与 Na-3DH-CDCA 的协同作用，因为在 12 小时后细菌数量减少。NMR 实验表明，当胆汁盐浓度高于临界胶束浓度（CMC）时，该胆汁盐衍生物和环丙沙星形成共聚物，这表明胆汁盐通过膜去稳定化增强环丙沙星细胞穿透的可能性，从而导致协同作用。
胆汁盐或衍生物与环丙沙星和特别是庆大霉素之间的协同相互作用代表了治疗鲍曼不动杆菌伤口感染的有前途的策略。
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