Diclofenac Sodium Restores the Sensitivity of Colistin-Resistant Gram-Negative Bacteria to Colistin

The continuous rise of multidrug-resistant (MDR) Gram-negative bacteria poses a severe threat to public health worldwide. Colistin(COL), employed as the last-line antibiotic against MDR pathogens, is now at risk due to the emergence of colistin-resistant (COL-R) bacteria, potentially leading to adverse patient outcomes. In this study, synergistic activity was observed when colistin and diclofenac sodium (DS) were combined and used against clinical COL-R strains of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), and Pseudomonas aeruginosa (P. aeruginosa) both in vitro and in vivo. The checkerboard method and time-killing assay showed that DS, when combined with COL, exhibited enhanced antibacterial activity compared to DS and COL monotherapies. Crystal violet staining and scanning electron microscopy showed that COL-DS inhibited biofilm formation compared with monotherapy. The in vivo experiment showed that the combination of DS and COL reduced bacterial loads in infected mouse thighs. Synergistic activity was observed when COL and DS were use in combination against clinical COL-R strains of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa both in vitro and in vivo. The synergistic antibacterial effect of the COL-DS combination has been confirmed by performing various in vitro and in vivo experiments, which provides a new treatment strategy for infections caused by MDR bacteria.