Platensimycin-Encapsulated Poly(lactic-co-glycolic acid) and Poly(amidoamine) Dendrimers Nanoparticles with Enhanced Anti-Staphylococcal Activity in Vivo
Platensimycin-Encapsulated Poly(lactic-co-glycolic acid) and Poly(amidoamine) Dendrimers Nanoparticles with Enhanced Anti-Staphylococcal Activity in Vivo
复制标题
板霉素包封的聚乳酸-乙醇酸和聚酰胺胺树枝状聚合物纳米颗粒具有增强的体内抗葡萄球菌活性
DOI：
10.1021/acs.bioconjchem.0c00121
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发表时间：
2020-05-01
影响因子：
4.7
通讯作者：
Huang, Yong
中科院分区：
文献类型：
--
作者：
Liu, Xingyun;Wang, Zhe;Huang, Yong
多重耐药病原体的严重细菌感染导致人员损失，危害公众健康。具有新作用模式的抗生素的发现，与纳米技术相结合，可能会为对抗多重耐药病原体提供一条有希望的途径。铂新霉素(Platensimycin，PTM)是一种高效的FabB/FabF的细菌脂肪酸生物合成抑制剂，是一种很有前途的抗耐药药物。然而，PTM的药代动力学较差，阻碍了其临床发展。在此，我们报道了一种纳米策略，将PTM包裹在两种纳米粒子(NPs)中：聚乳酸-乙醇酸(PLGA)和聚酰胺胺(PAMAM)树枝状大分子，以增强其体外和体内的抗菌活性。PTM包裹的纳米粒能有效地抑制金黄色葡萄球菌生物被膜的形成，并在巨噬细胞感染模型中比游离PTM杀灭更多的金黄色葡萄球菌。药代动力学研究表明，负载PTM的PLGA和PAMAM纳米粒的AUC(0-t)(曲线下面积)比游离PTM分别增加了4倍和2倍。在小鼠腹膜炎模型中，用两种负载PTM的纳米粒(10 mg/kg)腹腔注射治疗耐甲氧西林金黄色葡萄球菌感染的小鼠，可使它们完全存活，而当用游离PTM(10 mg/kg)治疗时，所有感染的小鼠都死亡。这些结果不仅表明负载PTM的纳米粒可能具有改善PTM不良药代动力学特性的巨大潜力，而且支持开发细菌脂肪酸合成酶抑制剂作为抗耐药病原体的有前途的抗生素的理论基础。
Serious bacterial infections by multi-drug-resistant pathogens lead to human losses and endanger public health. The discovery of antibiotics with new modes of action, in combination with nanotechnology, might offer a promising route to combat multi-drug-resistant pathogens. Platensimycin (PTM), a potent inhibitor of FabB/FabF for bacterial fatty acid biosynthesis, is a promising drug lead against many drug-resistant bacteria. However, the clinical development of PTM is hampered by its poor pharmacokinetics. Herein, we report a nanostrategy that encapsulated PTM in two types of nanoparticles (NPs) poly(lactic-co-glycolic acid) (PLGA) and poly(amidoamine) (PAMAM) dendrimer to enhance its antibacterial activity in vitro and in vivo. The PTM-encapsulated NPs were effective to inhibit Staphylococcus aureus biofilm formation, and killed more S. aureus in a macrophage cell infection model over free PTM. The pharmacokinetic studies showed that PTM-loaded PLGA and PAMAM NPs exhibited increased AUC(0-t) (area under the curve) (similar to 4- and 2-fold) over free PTM. In a mouse peritonitis model, treatment of methicillin-resistant S. aureus infected mice using both PTM-loaded NPs (10 mg/kg) by intraperitoneal injection led to their full survival, while all infected mice died when treated by free PTM (10 mg/kg). These results not only suggest that PTM-loaded NPs may hold great potential to improve the poor pharmacokinetic properties of PTM, but support the rationale to develop bacterial fatty acid synthase inhibitors as promising antibiotics against drug-resistant pathogens.