Owing to the increased tissue iron accumulation in patients with diabetes, microorganisms may activate high expression of iron-involved metabolic pathways, leading to the exacerbation of bacterial infections and disruption of systemic glucose metabolism. Therefore, an on-demand transdermal dosing approach that utilizes iron homeostasis regulation to combat antimicrobial resistance is a promising strategy to address the challenges associated with low administration bioavailability and high antibiotic resistance in treating infected diabetic wounds. Here, it is aimed to propose an effective therapy based on hemoglobin bionics to induce disturbances in bacterial iron homeostasis. The preferred “iron cargo” is synthesized by protoporphyrin IX chelated with dopamine and gallium (PDGa), and is delivered via a glucose/pH-responsive microneedle bandage (PDGa@GMB). The PDGa@GMB downregulates the expression levels of the iron uptake regulator (Fur) and the peroxide response regulator (perR) in Staphylococcus aureus, leading to iron nutrient starvation and oxidative stress, ultimately suppressing iron-dependent bacterial activities. Consequently, PDGa@GMB demonstrates insusceptibility to genetic resistance while maintaining sustainable antimicrobial effects (>90%) against resistant strains of both S. aureus and E. coli, and accelerates tissue recovery (<20 d). Overall, PDGa@GMB not only counteracts antibiotic resistance but also holds tremendous potential in mediating microbial-host crosstalk, synergistically attenuating pathogen virulence and pathogenicity.

中文翻译：

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基于血红蛋白仿生学的系统，通过铁稳态调节对抗慢性糖尿病伤口的抗生素耐药性


由于糖尿病患者组织铁积累增加，微生物可能激活铁相关代谢途径的高表达，导致细菌感染加剧和全身葡萄糖代谢破坏。因此，利用铁稳态调节来对抗抗菌素耐药性的按需透皮给药方法是解决治疗感染糖尿病伤口中低给药生物利用度和高抗生素耐药性相关挑战的一种有前途的策略。在此，目的是提出一种基于血红蛋白仿生学的有效疗法，以诱导细菌铁稳态紊乱。优选的“铁货物”由多巴胺和镓 (PDGa) 螯合的原卟啉 IX 合成，并通过葡萄糖/pH 响应微针绷带 (PDGa@GMB) 递送。 PDGa@GMB 下调金黄色葡萄球菌中铁摄取调节剂 (Fur) 和过氧化物反应调节剂 (perR) 的表达水平，导致铁营养缺乏和氧化应激，最终抑制铁依赖性细菌活动。因此，PDGa@GMB 表现出对遗传耐药性的不敏感性，同时对金黄色葡萄球菌和大肠杆菌的耐药菌株保持可持续的抗菌效果 (>90%)，并加速组织恢复 (<20 d)。总体而言，PDGa@GMB不仅可以抵消抗生素耐药性，而且在介导微生物-宿主串扰、协同减弱病原体毒力和致病性方面具有巨大潜力。