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载有黏菌素和氯硝柳胺的纳米乳剂及纳米乳凝胶用于耐黏菌素感染的有效治疗

Colistin-niclosamide-loaded nanoemulsions and nanoemulsion gels for effective therapy of colistin-resistant infections.

作者信息

Zhang Junkai, Wang Xilong, Li Pengliang, Gao Yanling, Wang Ruiyun, Li Shuaihua, Yi Kaifang, Cui Xiaodie, Hu Gongzheng, Zhai Yajun

机构信息

College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China.

Henan Vocational College of Agriculture, Zhengzhou, China.

出版信息

Front Vet Sci. 2024 Oct 23;11:1492543. doi: 10.3389/fvets.2024.1492543. eCollection 2024.

DOI:10.3389/fvets.2024.1492543
PMID:39507218
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11539104/
Abstract

Colistin (COL) is regarded as a last-resort treatment for infections by multidrug-resistant (MDR) Gram-negative bacteria. The emergence of colistin-resistant Enterobacterales poses a significant global public health concern. Our study discovered that niclosamide (NIC) reverses COL resistance in via a checkerboard assay. However, poor solubility and bioavailability of NIC pose challenges. In this study, we prepared a self-nanoemulsifying drug delivery system (SNEDDS) co-encapsulating NIC and COL. We characterized the physicochemical properties of the resulting colistin-niclosamide-loaded nanoemulsions (COL/NIC-NEs) and colistin-niclosamide-loaded nanoemulsion gels (COL/NIC-NEGs), assessing their antibacterial efficacy . The COL/NIC-NEs exhibited a droplet size of 19.86 nm with a zeta potential of -1.25 mV. COL/NIC-NEs have excellent stability, significantly enhancing the solubility of NIC while also demonstrating a pronounced sustained-release effect. Antimicrobial assays revealed that the MIC of COL in COL/NIC-NEs was reduced by 16-128 times compared to free COL. Killing kinetics and scanning electron microscopy confirmed enhanced antibacterial activity. Antibacterial mechanism studies reveal that the COL/NIC-NEs and COL/NIC-NEGs could enhance the bactericidal activity by damaging cell membranes, disrupting proton motive force (PMF), inhibiting multidrug efflux pump, and promoting oxidative damage. The therapeutic efficacy of the COL/NIC-NEs and COL/NIC-NEGs is further demonstrated in mouse intraperitoneal infection models with COL-resistant . To sum up, COL/NIC-NEs and COL/NIC-NEGs are a potentially effective strategies promising against COL-resistant infections.

摘要

黏菌素（COL）被视为治疗多重耐药（MDR）革兰氏阴性菌感染的最后手段。耐黏菌素肠杆菌的出现引起了全球重大公共卫生关注。我们的研究通过棋盘法发现，氯硝柳胺（NIC）可逆转 中的COL耐药性。然而，NIC的低溶解度和生物利用度带来了挑战。在本研究中，我们制备了一种共包封NIC和COL的自纳米乳化药物递送系统（SNEDDS）。我们对所得载黏菌素 - 氯硝柳胺纳米乳剂（COL/NIC - NEs）和载黏菌素 - 氯硝柳胺纳米乳凝胶（COL/NIC - NEGs）的理化性质进行了表征，评估了它们的抗菌效果。COL/NIC - NEs的液滴尺寸为19.86 nm，zeta电位为 - 1.25 mV。COL/NIC - NEs具有优异的稳定性，显著提高了NIC的溶解度，同时还表现出明显的缓释效果。抗菌试验表明，与游离COL相比，COL/NIC - NEs中COL的最低抑菌浓度（MIC）降低了16 - 128倍。杀菌动力学和扫描电子显微镜证实了抗菌活性增强。抗菌机制研究表明，COL/NIC - NEs和COL/NIC - NEGs可通过破坏细胞膜、扰乱质子动力势（PMF）、抑制多药外排泵以及促进氧化损伤来增强杀菌活性。在耐COL的小鼠腹腔感染模型中进一步证明了COL/NIC - NEs和COL/NIC - NEGs的治疗效果。综上所述，COL/NIC - NEs和COL/NIC - NEGs是对抗耐COL感染的潜在有效策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/e747171423cb/fvets-11-1492543-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/33a821b1ef3d/fvets-11-1492543-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/1b6d8c7fd787/fvets-11-1492543-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/806851e0d8ca/fvets-11-1492543-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/f12939414461/fvets-11-1492543-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/f5df9032df1f/fvets-11-1492543-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/d3e4ebd4b86a/fvets-11-1492543-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/dc38c4d64670/fvets-11-1492543-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/e747171423cb/fvets-11-1492543-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/33a821b1ef3d/fvets-11-1492543-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/1b6d8c7fd787/fvets-11-1492543-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/806851e0d8ca/fvets-11-1492543-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/f12939414461/fvets-11-1492543-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/f5df9032df1f/fvets-11-1492543-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/d3e4ebd4b86a/fvets-11-1492543-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/dc38c4d64670/fvets-11-1492543-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b8e/11539104/e747171423cb/fvets-11-1492543-g008.jpg

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