Chitosan-dextran sulfate nanocapsules for enhanced tigecycline efficacy against non-typhoidal Salmonella enterica

Abstract Salmonella is a significant foodborne pathogen found worldwide. Resistance to tigecycline (TGC) has been increasingly reported. The emergence of multidrug-resistant (MDR) non-typhoidal Salmonella (NTS) with high efflux pump activity necessitates the development of efficient drug delivery systems. This study investigates the potential of tigecycline-loaded chitosan-dextran sulfate (CD-TGC) nanocapsules to combat NTS in vitro and in vivo mouse peritonitis model. Antimicrobial susceptibility and efflux pump activity of NTS isolates were tested. S. enterica serotype Bredeney isolates that showed high efflux index and high multiple antibiotic resistance index were subjected to whole genome sequencing (WGS), revealing numerous resistance genes, including APH(3’’), MarA, MarB, MarR, Alr, Ddl, dxr, BcrC, AcrAB-TolC, AcrAD-TolC, gidB, GdpD, PgsA, H-NS, and OxyR. Additionally, the presence of resistance-nodulation-cell division (RND) efflux pumps, major facilitator superfamily (MFS), and ATP-binding cassette (ABC) efflux pumps were confirmed. CD-TGC demonstrated significantly lower minimum inhibitory concentrations (MIC 0.5–1 µg/mL) against NTS strains compared to tigecycline (TGC) alone (MIC 32–128 µg ̸mL). CD-TGC decreased MIC 7-fold, from 128 to 1 µg/mL, in one S. Typhimurium strain. In the other 11 strains, CD-TGC reduced the TGC MIC 6-fold, from 64 to 1 µg/mL (n = 6) and 32 to 0.5 µg/mL (n = 5). Time-kill assays confirmed enhanced bactericidal activity. Furthermore, CD-TGC downregulated the expression of ramA and acrB efflux pump genes. In a mouse model of S. Typhimurium infection, CD-TGC treatment effectively reduced bacterial burden in the liver and intestine, minimized liver and kidney function alterations, and decreased mortality rates compared to tigecycline and unloaded CD nanocapsules. The survival rates of mice were 100% in the CD-TGC treatment group and 40% in the TGC treatment group. Histopathological analysis confirmed reduced tissue damage in the CD-TGC-treated group. The findings indicate that CD-TGC nanocapsules offer a promising drug delivery strategy for treating intracellular Salmonella infections, overcoming resistance mechanisms and improving treatment outcomes where tigecycline alone is less effective.