53 / 2024-10-23 14:47:07

Amphiphilic mPEG-PLGA copolymer nanoparticles Co-Delivering Colistin and Niclosamide to Treat Colistin-Resistant Gram-Negative Bacteria Infections

Colistin is the antibiotic of last resort for the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections that cannot be treated with other clinically available antibiotics. However, the high susceptibility to drug resistance and high toxicity seriously limits its application. Here, we found that niclosamide can reverse the resistant phenotype of colistin-resistant bacteria through a checkerboard test. However, the challenge remains in providing multiple therapeutic drugs at relevant doses. Nanodelivery systems offer opportunities to address these issues. In this study, we designed and prepared a nanosystem capable of co-loading two drugs (colistin and niclosamide) with different physicochemical properties into mPEG-PLGA nanoparticles (COL/NIC-mPEG-PLGA-NPs) to overcome colistin resistance and alleviate its toxicity in multiple colistin-resistant bacteria. Mechanistic studies revealed that the COL/NIC-mPEG-PLGA-NPs enhanced the affinity of delivered COL to the modified membrane of colistin-resistant bacteria. The increased membrane permeability caused by colistin promotes an influx of niclosamide, which reduces efflux pump activity and generates intracellular ROS stress, eliminating colistin-resistant bacteria. More importantly, a colistin-resistant mouse peritonitis-sepsis infection model demonstrated the excellent therapeutic efficacy of COL/NIC-mPEG-PLGA-NPs. In addition, the nanoparticles proved non-toxic both in vitro and in vivo. Overall, our study has profound insights into the use of nanosystems with high biosafety for the treatment of infections caused by colistin-resistant bacteria.