Colistin and Oxyclozanide co-loaded PLGA nano-microspheres to reverse colistin resistance can effectively treat colistin-resistant Escherichia coli infections

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Colistin (COL) is widely recognized as the last line of defense for treating MDR-negative bacterial infections, but currently, bacteria have a very serious resistance to COL. The combination of antibacterial drugs and adjuvant drugs can reverse drug resistance, enhance antibacterial activity, and improve therapeutic effects. It is currently regarded as a new safe and effective strategy for controlling drug resistance. In this study, we found that the combination of Oxyclozanide (OXY) and colistin can effectively reverse colistin resistance. For multiple colistin resistant Escherichia coli ( E. coli ) strains, COL-OXY-PLGA @MS significantly reduced the MIC of COL monotherapy (8 < MIC<64) by 40–160 times. The prepared COL-OXY-PLGA@MS had particle sizes of 140–160 nm, PDI of 0.03–0.2, COL loading of 5.14 % and OXY loading of 2.93 %. The release rate of COL in COL-OXY-PLGA@MS at 72 h was 39.31 %, and there was no burst release. Cytotoxicity assay, hemolysis test and long-term injection tests in mice have proved that COL-OXY-PLGA@MS has good safety and biocompatibility. It was clearly observed by SEM that the COL-OXY-PLGA@MS group disrupted E. coli 58 cells under 1 h of action with obvious exudation of contents, and large number of cells ruptured at 4 h and 12 h. COL-OXY-PLGA@MS significantly reduced mortality rate after E. coli infection in mice. This study successfully prepared COL-OXY-PLGA@MS with high safety and strong antibacterial effect, which has great potential in the treatment of infections caused by color-resistant Gram-negative bacteria and provides a new and important strategy for the clinical application of colistin. Graphical Abstract Schematic diagram of colistin and oxyclozanide co-loaded PLGA nano-microspheres and treatment regimen of colissin-resistant E. coli peritoneal infection in mice using COL-OXY-PLGA@MS. Create using biorender.com . Insert Table of Contents artwork here 1. Characterization of the antibacterial activity of the combined use of colistin (COL) and oxyclozanide (OXY) 2. Establishment of analytical methods before synthesis of COL-OXY-PLGA@MS 3. Synthesis and optimization of COL-OXY-PLGA@MS 4. Characterization of COL-OXY-PLGA@MS 5. Encapsulation efficiency and Drug loading capacity 6. In Vitro and in Vivo Biocompatibility of COL-OXY-PLGA@MS 7. In Vitro bacteriostatic action of COL-OXY-PLGA@MS 8. In vivo antibacterial activity against colistin-resistant E. coli infection • This study demonstrated that a very low concentration of oxyclozanide could reverse bacterial colistin resistance, enhance the antibacterial activity of colistin. • The COL-OXY-PLGA@MS prepared simultaneously loaded with colistin and Oxyclozanide achieved a novel combination of colistin and adjuvant. • This study demonstrated the good biocompatibility of COL-OXY-PLGA@MS by both in vivo and in vitro methods, including cytotoxicity, hemolysis test, and long-term injection in mice. • COL-OXY-PLGA@MS significantly reduces the MIC of colistin, significantly lowers the mortality rate of Escherichia coli infection in mice, effectively protects the intestines and other organs, and has the potential to be a new type of antibacterial drug.