PDF(Pubmed)
Abstract：
Hematoma, a risk factor of implant-associated infections (IAIs), creates a Fe-rich environment following implantation, which proliferates the growth of pathogenic bacteria. Fe metabolism is a major vulnerability for pathogens and is crucial for several fundamental physiological processes. Herein, a deferiprone (DFP)-loaded layered double hydroxide (LDH)-based nanomedicine (DFP@Ga-LDH) that targets the Fe-rich environments of IAIs is reported. In response to acidic changes at the infection site, DFP@Ga-LDH systematically interferes with bacterial Fe metabolism via the substitution of Ga3+ and Fe scavenging by DFP. DFP@Ga-LDH effectively reverses the Fe/Ga ratio in Pseudomonas aeruginosa, causing comprehensive interference in various Fe-associated targets, including transcription and substance metabolism. In addition to its favorable antibacterial properties, DFP@Ga-LDH functions as a nano-adjuvant capable of delaying the emergence of antibiotic resistance. Accordingly, DFP@Ga-LDH is loaded with a siderophore antibiotic (cefiderocol, Cefi) to achieve the antibacterial nanodrug DFP@Ga-LDH-Cefi. Antimicrobial and biosafety efficacies of DFP@Ga-LDH-Cefi are validated using ex vivo human skin and mouse IAI models. The pivotal role of the hematoma-created Fe-rich environment of IAIs is highlighted, and a nanoplatform that efficiently interferes with bacterial Fe metabolism is developed. The findings of the study provide promising guidance for future research on the exploration of nano-adjuvants as antibacterial agents.
摘要：
血肿,植入物相关感染(IAIs)的危险因素，植入后创造了富含铁的环境，它促进了致病菌的生长。铁代谢是病原体的主要弱点，对于几个基本的生理过程至关重要。在这里，据报道，基于去铁酮（DFP）的层状双氢氧化物（LDH）的纳米药物（DFP@Ga-LDH）靶向IAIs的富含Fe的环境。为了应对感染部位的酸性变化，DFP@Ga-LDH通过取代Ga3和DFP清除Fe来系统地干扰细菌Fe的代谢。DFP@Ga-LDH有效地逆转了铜绿假单胞菌中的Fe/Ga比率，对各种铁伴生目标造成综合干扰，包括转录和物质代谢。除了其良好的抗菌性能，DFP@Ga-LDH用作能够延迟抗生素抗性出现的纳米佐剂。因此，DFP@Ga-LDH装载有铁载体抗生素(头孢地洛，头孢)实现抗菌纳米药物DFP@Ga-LDH-头孢。使用离体人皮肤和小鼠IAI模型验证DFP@Ga-LDH-Cefi的抗微生物和生物安全性功效。强调了血肿产生的IAIs富铁环境的关键作用，并开发了有效干扰细菌铁代谢的纳米平台。研究结果为今后探索纳米佐剂作为抗菌剂的研究提供了有希望的指导。
