Chen Yujun, Xu Mao, Pan Jieyi, Liao Yuan, Na Jintong, Li Pengyu, Sun Yingying, Yu Shihui, Zhao Yongxiang, Hu Haiyan
State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
ACS Appl Mater Interfaces. 2025 Jan 29;17(4):5695-5709. doi: 10.1021/acsami.4c14991. Epub 2025 Jan 13.
() infections are increasingly challenging due to their propensity to form biofilms and low outer membrane permeability, especially in chronically infected patients with thick mucus. exhibits multiple drug resistance mechanisms, making it one of the most significant global public health threats. In this study, we found that moxifloxacin (MXC) and antibacterial peptides (ε-poly-l-lysine, ε-PLL) exhibited a synergistic effect against multidrug-resistant (MDR-). MXC was combined with ε-PLL to prepare lipase-responsive nanoparticles (MCIP/(PEG-PCL)/PLL NPs) with a weakly negative charge. The weakly negatively charged MCIP/(PEG-PCL)/PLL NPs demonstrated remarkable mucus and biofilm penetration capabilities, thereby overcoming one of the adaptive drug resistance mechanisms. MCIP/(PEG-PCL)/PLL NPs improved the outer and inner membrane permeability and inhibited the expression of the efflux pump MexAB-OprM gene in MDR-, thereby overcoming mechanisms of both intrinsic and acquired drug resistance. Meanwhile, the nanoparticles demonstrated an ability to reduce repeated infections with MDR-. Additionally, the bacterial burden in the lungs of mice treated with MCIP/(PEG-PCL)/PLL NPs was significantly lower than that in the MXC group, resulting in a 99% clearance rate. Notably, MCIP/(PEG-PCL)/PLL NPs showed no toxicity toward BEAS-2B cells or RAW 267.4 cells, nor did they adversely affect pulmonary function or major organs. This study demonstrated the potential of the nanodrug delivery system composed of the antibiotic moxifloxacin and the antibacterial peptide ε-PLL in addressing the clinical challenges of treating chronic pulmonary infections caused by MDR-.
由于其形成生物膜的倾向和较低的外膜通透性，（某病原体）感染正变得越来越具有挑战性，尤其是在患有浓稠黏液的慢性感染患者中。（该病原体）表现出多种耐药机制，使其成为全球最重大的公共卫生威胁之一。在本研究中，我们发现莫西沙星（MXC）和抗菌肽（ε-聚-L-赖氨酸，ε-PLL）对多重耐药（某病原体）（MDR-）表现出协同作用。将MXC与ε-PLL结合制备具有弱负电荷的脂肪酶响应性纳米颗粒（MCIP/(PEG-PCL)/PLL NPs）。带弱负电荷的MCIP/(PEG-PCL)/PLL NPs表现出显著的黏液和生物膜穿透能力，从而克服了一种适应性耐药机制。MCIP/(PEG-PCL)/PLL NPs提高了外膜和内膜的通透性，并抑制了MDR-中流出泵MexAB-OprM基因的表达，从而克服了固有和获得性耐药机制。同时，这些纳米颗粒表现出减少MDR-重复感染的能力。此外，用MCIP/(PEG-PCL)/PLL NPs治疗的小鼠肺部细菌负荷明显低于MXC组，清除率达99%。值得注意的是，MCIP/(PEG-PCL)/PLL NPs对BEAS-2B细胞或RAW 267.4细胞没有毒性，也没有对肺功能或主要器官产生不利影响。本研究证明了由抗生素莫西沙星和抗菌肽ε-PLL组成的纳米药物递送系统在应对治疗由MDR-引起的慢性肺部感染的临床挑战方面的潜力。
