School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China.
Department of Immunology and Microbiology, Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
ACS Nano. 2023 Aug 22;17(16):15411-15423. doi: 10.1021/acsnano.3c00981. Epub 2023 Aug 3.
Colistin is the last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections that are untreatable by other clinically available antibiotics. However, the recently merged plasmid-borne gene mobilized colistin resistance () leads to modification of the colistin target (i.e., bacterial membrane), greatly compromising the therapy outcome of colistin. To address this unmet clinical need, a nanocomplex (CMS-pEt_20 NP) of anionic prodrug colistin methanesulfonate (CMS) and guanidinium-functionalized cationic polymer pEt_20 is developed through facile self-assembly for co-delivering an antibiotic and antimicrobial polymer with membrane affinity to reverse colistin resistance. The CMS-pEt_20 NP formation enables reversal of colistin resistance and complete killing of clinically isolated -positive colistin-resistant bacteria including MDR and , while monotreatment of polymer or antibiotic at equivalent doses exhibits no antibacterial activity. Mechanistic studies reveal that the CMS-pEt_20 NP enhanced the affinity of delivered CMS to the modified membrane of colistin-resistant bacteria, reviving the membrane lytic property of colistin. The increased membrane permeability caused by colistin in turn promotes an influx of pEt_20 to generate intracellular ROS stress, resulting in elimination of colistin-resistant bacteria. More importantly, a colistin-resistant mouse peritonitis-sepsis infection model demonstrates the excellent therapeutic efficacy of CMS-pEt_20 NP with 100% survival of the infected mouse. In addition, the nanocomplex is proven not toxic both and . Taken together, the self-assembled antibiotic-polymer nanocomplex with two complementary antibacterial mechanisms successfully reverses the colistin resistance phenotype in bacteria, and it can be a potential strategy to treat untreatable colistin-resistant MDR bacterial infections.
黏菌素是治疗其他临床可用抗生素无法治疗的多重耐药（MDR）革兰氏阴性细菌感染的最后手段抗生素。然而，最近合并的质粒携带基因可移动黏菌素耐药性（）导致黏菌素靶位（即细菌膜）的修饰，极大地影响了黏菌素治疗效果。为了解决这一未满足的临床需求，通过简便的自组装开发了带负电荷的前药黏菌素甲磺酸盐（CMS）和胍基功能化阳离子聚合物 pEt_20 的阴离子纳米复合物（CMS-pEt_20 NP），用于共同递送具有膜亲和力的抗生素和抗菌聚合物，以逆转黏菌素耐药性。CMS-pEt_20 NP 的形成能够逆转黏菌素耐药性，并完全杀死包括 MDR 和在内的临床分离的阳性黏菌素耐药细菌，而在等效剂量下单独使用聚合物或抗生素则没有抗菌活性。机制研究表明，CMS-pEt_20 NP 增强了递送至耐药细菌改性膜的 CMS 的亲和力，恢复了黏菌素的膜裂解特性。黏菌素引起的细胞膜通透性增加反过来又促进 pEt_20 的内流，从而产生细胞内 ROS 应激，导致黏菌素耐药菌的消除。更重要的是，黏菌素耐药性小鼠腹膜炎-败血症感染模型表明，CMS-pEt_20 NP 具有出色的治疗效果，感染小鼠的存活率为 100%。此外，该纳米复合物已被证明在体内和体外均无毒。综上所述，具有两种互补抗菌机制的自组装抗生素-聚合物纳米复合物成功地逆转了细菌中的黏菌素耐药表型，它可能是治疗无法治疗的黏菌素耐药性 MDR 细菌感染的潜在策略。
