Hubei Key Laboratory of Material Chemistry and Service Failure, Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
College of Chemistry, Liaoning University, Shenyang 110036, PR China.
ACS Macro Lett. 2023 Sep 19;12(9):1193-1200. doi: 10.1021/acsmacrolett.3c00365. Epub 2023 Aug 17.
The stalling development of antibiotics, especially against intrinsically resistant Gram-negative pathogens associated with outer membranes, leads to an emerging antibiotic crisis across the globe. To breathe life into existing drugs, we herein report a hypoxia-responsive nanoparticle (NP) that encapsulates a hydrophobic antibiotic, rifampicin, and a cationic potentiator, polysulfonium. The simultaneous release of antibiotics and potentiators can be promoted and inhibited in response to the severity of bacterial-induced hypoxia, leading to antimicrobial dosing in a precision manner. Under the synergism of polysulfoniums with membrane-disruption capability, the NPs can intensively decrease the antibiotic dose by up to 66-95% in eliminating planktonic Gram-negative bacteria and achieve an 8-log reduction of bacteria in mature biofilms at rifampicin MIC. The NP formulation demonstrates that precision dosing of antibiotics and potentiators regulated by hypoxia provides a promising strategy to maximize efficacy and minimize toxicity in treating Gram-negative bacterial infection.
抗生素的发展陷入停滞，尤其是针对与外膜相关的固有耐药革兰氏阴性病原体的抗生素，这导致了全球范围内抗生素危机的出现。为了使现有药物重获生机，我们在此报告了一种缺氧响应纳米颗粒（NP），它包封了一种疏水性抗生素利福平（rifampicin）和一种阳离子增效剂聚磺（polysulfonium）。抗生素和增效剂的同时释放可以根据细菌诱导缺氧的严重程度来促进和抑制，从而以精确的方式进行抗菌药物剂量给药。在具有膜破坏能力的聚磺协同作用下，NP 可以将消除浮游革兰氏阴性菌所需的抗生素剂量最多减少 66-95%，并在利福平 MIC 下实现成熟生物膜中细菌减少 8 个对数级。该 NP 制剂表明，通过缺氧调节的抗生素和增效剂的精确给药为治疗革兰氏阴性菌感染提供了一种有前途的策略，可以最大限度地提高疗效并最小化毒性。
