Transformable nano-antibiotics for mechanotherapy and immune activation against drug-resistant Gram-negative bacteria

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) which 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 (LPS) 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 innate and adaptive immunity. TNA kills Gram-negative bacteria in vitro and in vivo with undetectable resistance through multiple bactericidal..., ,

针对革兰氏阴性菌（Gram-negative bacteria）的抗生素候选药物匮乏，叠加抗生素耐药性的加剧态势，已然构成全球性公共健康隐患。此类细菌的防控难点在于其独特的外膜结构：该结构可作为抗生素的不透性屏障，同时隔离抗原呈递过程。我们研发了一种可转化型纳米抗生素（transformable nano-antibiotics, TNA）：该制剂在靶向革兰氏阴性菌的β桶状组装机器A（β-barrel assembly machine A, BamA）与脂多糖（lipid polysaccharides, LPS）后，可从无毒纳米颗粒转化为具备合理刚性的杀菌性纳米纤维，其杨氏模量（Young’s modulus）为21.6 ± 5.9 MPa。完成形态转化后，该TNA可穿透并破坏细菌包膜，干扰电子传递通路与多条保守的生物合成及代谢途径，促使细菌抗原从外膜释放，进而激活固有免疫与适应性免疫。TNA可在体外（in vitro）与体内（in vivo）杀灭革兰氏阴性菌，且通过多重杀菌机制未检测到耐药性产生……