Hypoxia-sensitive adjuvant loaded liposomes enhance the antimicrobial activity of azithromycin via phospholipase-triggered releasing for Pseudomonas aeruginosa biofilms eradication.
Hypoxia-sensitive adjuvant loaded liposomes enhance the antimicrobial activity of azithromycin via phospholipase-triggered releasing for Pseudomonas aeruginosa biofilms eradication.
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DOI：
10.1016/j.ijpharm.2022.121910
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发表时间：
2022-06
影响因子：
5.8
通讯作者：
Yiqin Rao;Yingying Sun;Pengyu Li;Mao Xu;Xiaonan Chen;Yalong Wang;Yan Chen;Xin Deng;Shihui Yu;Haiyan Hu
中科院分区：
文献类型：
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作者：
Yiqin Rao;Yingying Sun;Pengyu Li;Mao Xu;Xiaonan Chen;Yalong Wang;Yan Chen;Xin Deng;Shihui Yu;Haiyan Hu
强健的生物被膜和复杂的呼吸道环境，加上浓痰、局部缺氧和持续炎症，导致铜绿假单胞菌引起的慢性肺部感染难以治愈。为此，我们提出了一种由阿齐霉素(AZI)、佐剂(2-硝基咪唑衍生物，6-NIH)和生物膜分散剂(一氧化氮供体，DETA NOate)共混而成的抗生素佐剂脂质体(NANO@PS-LP)。具有负电荷表面和良好亲水性的Nano@PS-LPs可以很容易地透过痰液层，然后在生物膜周围的微环境中被过表达的磷脂酶A2(PLA2)触发分解。DETA NONOate产生的一氧化氮促进P。铜绿假单胞菌扩散。在低氧条件下，6-NIH被还原为2-氨基咪唑衍生物(6-AIH)，从而作为AZI的佐剂来增强AZI的抗菌活性。结果表明，Nano@PS-LPs能显著消除成熟P。铜绿假单胞菌被膜能有效杀灭分散的细菌，抑制幸存者的新陈代谢，预防肺炎。铜绿假单胞菌与呼吸道上皮细胞黏附，从而抑制复发感染。此外，Nano@PS-LPs在杀灭Azi抗性P方面表现出显著的优势。铜绿假单胞菌和去除它们的生物膜。总之，Nano@PS-LPs为治疗顽固性假单胞菌肺部感染和克服相关耐药性提供了一种潜在的纳米策略。
Robust biofilms and the complex airway environment with thick sputum, local hypoxia and persistent inflammation induce the intractability of chronic pulmonary infections caused byPseudomonas aeruginosa(P. aeruginosa). Herein, we proposed a type of antibiotic-adjuvant liposomes (NANO@PS-LPs), co-incorporating azithromycin (AZI), adjuvant (2-nitroimidazole derivative, 6-NIH) and biofilm dispersant (nitric oxide donor, DETA NONOate). NANO@PS-LPs possessing negatively-charged surface and good hydrophilicity could easily penetrate through the sputum layer, then disassembled triggered by overexpressed phospholipase A2(PLA2) in the microenvironment around biofilms. Nitric oxide produced by DETA NONOate promotedP. aeruginosabiofilms dispersal. 6-NIH was reduced to 2-aminomidazole derivative (6-AIH) under a hypoxic condition, and hence acted as an AZI adjuvant to enhance the antibacterial activity of AZI. It was found that NANO@PS-LPs could significantly eliminate matureP. aeruginosabiofilms, effectively kill dispersed bacteria, inhibit the metabolism of survivors and preventP. aeruginosaadherence to airway epithelial cells, accordingly restrain recurrent infections. Additionally, NANO@PS-LPs performed a remarkable advantage in killing AZI-resistantP. aeruginosaand removing their biofilms. In summary, NANO@PS-LPs present a potential nano-strategy to treat stubborn pseudomonal pulmonary infections and overcome correlative drug resistance.