Synergistic activity of colistin combined with PFK-158 against colistin-resistant and colistin-susceptible Gram-negative bacteria

Abstract

Background: The emergence of colistin resistance among Gram-negative bacteria poses a serious public health threat and warrants immediate action. Therefore, it is necessary to enhance the antibacterial activity of colistin through the combination with other drugs. In this study, we demonstrate the synergistic activity of colistin combined with PFK-158 against colistin-susceptible but more importantly against colistin-resistant Gram-negative bacteria, including non-fermenting bacteria (P. aeruginosa, A. baumannii) and Enterobacteriaceae (E. coli and K. pneumoniae).Methods: 18 colistin-resistant and 12 colistin-susceptible Gram-negative bacteria were collected as the experimental strains, and the minimum inhibitory concentrations (MICs) of colistin and PFK-158 against all strains were determined by the broth microdilution method. The MICs of routine antimicrobial agents including aztreonam (ATM), ceftazidime (CAZ), cefepime (FEP), imipenem (IMP), ciprofloxacin (CIP), levofloxacin (LVX), gentamicin (GEN), tobramycin (TOB) for all 30 experimental strains were determined by bioMerieux VITEK-2 (BioMérieux, Marcy-l’Étoile, France). The synergistic activity of colistin combined with PFK-158 in vitro was assessed using the checkerboard assay and the time-kill assays.Results: The results of the checkerboard assay showed that when colistin was used in combination with PFK-158, synergistic activity was observed against the 18 colistin-resistant and the 8 colistin-susceptible Gram-negative bacteria, and the remaining 4 colistin-susceptible strains showed additive activity. No irrelevant activity and antagonistic activity was observed for all strains. The results of the time-killing assays presented that the killing activity against the colistin-resistant Gram-negative bacterium were evident for the combination of colistin and PFK-158, compared with the groups adding colistin or PFK-158 alone. Conclusions: In conclusion, our results strongly exhibited that the combination of colistin and PFK-158 displayed the significant synergistic activity against all tested colistin-resistant and most colistin-susceptible Gram-negative strains. PFK-158 was found to potentiate the antibacterial activity of colistin against a wide panel of colistin-resistant and colistin-susceptible Gram-negative strains no matter what species (including non-fermenting bacteria and Enterobacteriaceae). It may be a potential new choice for the treatment of infections caused by the clinical Gram-negative strains.