Transformable nano-antibiotics for mechanotherapy and immune activation against drug-resistant Gram-negative bacteria.
Transformable nano-antibiotics for mechanotherapy and immune activation against drug-resistant Gram-negative bacteria.
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DOI：
10.1126/sciadv.adg9601
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发表时间：
2023-08-25
期刊：
影响因子：
13.6
通讯作者：
Li, Na
中科院分区：
文献类型：
--
作者：
Li, Rong Sheng;Liu, Jiahui;Wen, Cong;Shi, Yaru;Ling, Jian;Cao, Qiue;Wang, Lei;Shi, Hu;Huang, Cheng Zhi;Li, Na
针对革兰氏阴性菌的抗生素候选物的缺乏和抗生素耐药性的上升造成了全球健康问题。挑战在于独特的革兰氏阴性细菌外膜，该外膜为抗生素提供不可渗透的屏障并隔离抗原呈递。我们设计了一种可转化的纳米抗生素（TNA），它可以在革兰氏阴性菌的β-桶组装机A（BamA）和脂多糖（LPS）的作用下，从无毒的纳米颗粒转化为具有合理刚度（杨氏模量为21.6 ± 5.9 MPa）的杀菌纳米纤维。在形态学转化后，TNA可以穿透并破坏细菌包膜，破坏电子传递和多种保守的生物合成和代谢途径，使细菌抗原从外膜释放，并随后激活先天性和适应性免疫。TNA通过多种杀菌作用模式在体外和体内杀死革兰氏阴性菌，且耐药性不可检测。TNA治疗诱导的疫苗接种导致快速和持久的免疫应答，防止致命的再感染。物理破坏细菌包膜有效地避免了细菌耐药性，降低了再感染的死亡率。
The dearth of antibiotic candidates against Gram-negative bacteria and the rise of antibiotic resistance create a global health concern. The challenge lies in the unique Gram-negative bacterial outer membrane that provides the impermeable barrier for antibiotics and sequesters antigen presentation. We designed a transformable nano-antibiotics (TNA) that can transform from nontoxic nanoparticles to bactericidal nanofibrils with reasonable rigidity (Young’s modulus, 21.6 ± 5.9 MPa) after targeting β-barrel assembly machine A (BamA) and lipid polysaccharides (LPSs) of Gram-negative bacteria. After morphological transformation, the TNA can penetrate and damage the bacterial envelope, disrupt electron transport and multiple conserved biosynthetic and metabolic pathways, burst bacterial antigen release from the outer membrane, and subsequently activate the innate and adaptive immunity. TNA kills Gram-negative bacteria in vitro and in vivo with undetectable resistance through multiple bactericidal modes of action. TNA treatment–induced vaccination results in rapid and long-lasting immune responses, protecting against lethal reinfections. Physical disruption of bacterial envelope effectively avoids bacterial resistance and reduces mortality from reinfection.
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