Abstract
ABSTRACTThe spread of multidrug-resistant (MDR) Gram-negative bacteria (GNB) has led to serious public health problems worldwide. Colistin, as a “last resort” for the treatment of MDR bacterial infections, has been used significantly in recent years and has led to the continuous emergence of colistin-resistant strains. In this study, we aimed to investigate the synergistic effect on the antimicrobial and antibiofilm activities of a colistin/furanone C-30 combination against colistin-resistant GNB in vitro and in vivo. According to antimicrobial resistance profiles, most of the colistin-resistant strains we collected showed MDR phenotypes. The checkerboard method and time-kill curve showed that the combination with furanone C-30 increases the antibacterial activity of colistin significantly. In addition, the furanone C-30/colistin combination can not only inhibit the formation of bacterial biofilm but also has a better eradication effect on preformed mature biofilms. The result of scanning electron microscopy (SEM) demonstrated that the furanone C-30/colistin combination led to a significant reduction in the number of cells in biofilms. Furthermore, furanone C-30 at 50 μg/ml did not cause any additional toxicity to RAW264.7 cells according to a cytotoxicity assay. In in vivo infection experiments, the furanone C-30/colistin combination increased the survival rate of infected Galleria mellonella larvae as well as decreased the microbial load in a mouse thigh infection model. The synergistic effect of the furanone C-30/colistin combination against colistin-resistant GNB is encouraging, and this work may shed light on a new therapeutic approach to combat colistin-resistant pathogens.IMPORTANCE Colistin is among the few antibiotics effective against multidrug-resistant Gram-negative bacteria (GNB) clinical isolates. However, colistin-resistant GNB strains have emerged in recent years. Therefore, the combination of colistin and nonantibacterial drugs has attracted much attention. In this study, the furanone C-30/colistin combination showed good antibacterial and antibiofilm activity in vitro and in vivo. In addition, increased membrane permeability leads to the synergistic effect of the furanone C-30/colistin combination. Because of the low cytotoxicity of furanone C-30, this combination has good application prospects in clinical anti-infective therapy. This finding might shed light on the discovery of combination therapy for infections caused by colistin-resistant GNB pathogens.
Highlights
The spread of multidrug-resistant (MDR) Gram-negative bacteria (GNB) has led to serious public health problems worldwide
The result showed that furanone C-30 displayed weak or no antimicrobial activity against colistin-resistant GNB (MIC $ 50 mg/ml)
The drug resistance of E. coli and K. pneumoniae is more severe than P. aeruginosa, as they are resistant to almost all the antibiotics commonly used in the clinic
Summary
The spread of multidrug-resistant (MDR) Gram-negative bacteria (GNB) has led to serious public health problems worldwide. As a “last resort” for the treatment of MDR bacterial infections, has been used significantly in recent years and has led to the continuous emergence of colistin-resistant strains. Colistin is a polymyxin antibiotic (polymyxin E) that has emerged as a “last resort” drug for the treatment of MDR Gram-negative bacteria (GNB) and is being widely used in clinical anti-infective treatment. The synthetic furanone C-30 was proven to decrease acyl-homoserine lactone-based and autoinducer 2-based QS signaling as well as alleviate the virulence of P. aeruginosa in a mouse pulmonary infection model [9, 12] These brominated furanones interrupt QS by interacting with transcriptional regulators that suppress virulence [13] without affecting bacterial growth [14]
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