Self-assembled and intestine-targeting florfenicol nano-micelles effectively inhibit drug-resistant Salmonella typhimurium, eradicate biofilm, and maintain intestinal homeostasis

Antimicrobial resistance (AMR) is a growing public health crisis that requires innovative solutions. Emerging multidrug resistant (MDR) <i>Salmonella typhimurium</i> has raised concern for its effect on pathogenic infection and mortality in humans caused by enteric diseases. To combat these MDR <i>Salmonella typhimurium</i> pathogens, highly effective and broad-spectrum antibiotics such as flufenicol (FFC) need to be evaluated for their potent antibacterial activity against <i>Salmonella typhimurium</i>. However, the low solubility and low oral bioavailability of flufenicol need to be addressed to better combat AMR. In this work, we develop a novel nano-formulation, flufenicol nano-micelles (FTPPM), which are based on d-α-tocopherol polyethylene glycol 1,000 succinate (TPGS)/poloxamer 188 (P188), for the targeted treatment of biofilms formed by drug-resistant <i>Salmonella typhimurium</i> in the intestine. Herein, FTPPM were prepared via a thin film hydration method. The preparation process for the mixed micelles is simple and convenient compared with other existing nanodrug delivery systems, which can further decrease production costs. The optimized FTPPM demonstrated outstanding stability and sustained release. An evaluation of the <i>in vivo</i> anti-drug-resistant <i>Salmonella typhimurium</i> efficacy demonstrated that FTPPM showed a stronger efficacy (68.17 %) than did florfenicol-loaded TPGS polymer micelles (FTPM), flufenicol active pharmaceutical ingredients (FFC-API), and flufenicol commercially available medicine (FFC-CAM), and also exhibited outstanding biocompatibility. Notably, FTPPM also inhibited drug-resistant <i>Salmonella typhimurium</i> from forming biofilms. More importantly, FTPPM effectively restored intestinal flora disorders induced by drug-resistant <i>Salmonella typhimurium</i> in mice. In summary, FTPPM significantly improved the solubility and oral bioavailability of florfenicol, enhancing its efficacy against drug-resistant <i>Salmonella typhimurium</i> both <i>in vitro</i> and <i>in vivo</i>. FTPPM represent a promising drug-resistant <i>Salmonella typhimurium</i> treatment for curbing bacterial resistance via oral administration.