Synergistic Activity of Colistin Combined With Auranofin Against Colistin-Resistant Gram-Negative Bacteria.

Xiaoxuan Feng,Yulin Zhang,Chunlei Wang,Bin Cao,Yingmei Liu,Haibo Li,Shuai Liu,Yang Wang,Lingxiao Sun

doi:10.3389/fmicb.2021.676414

Abstract

Colistin-resistant (Col-R) bacteria are steadily increasing, and are extremely difficult to treat. New drugs or therapies are urgently needed to treat infections caused by these pathogens. Combination therapy with colistin and other old drugs, is an important way to restore the activity of colistin. This study aimed to investigate the activity of colistin in combination with the anti-rheumatic drug auranofin against Col-R Gram-negative bacteria. The results of checkerboard analysis demonstrated that auranofin synergized with colistin against Col-R Gram-negative bacteria. Time-kill assays showed significant synergistic antimicrobial activity of colistin combined with auranofin. Electron microscopy revealed that the combination resulted in more cellular structural alterations compared to each drug alone. Auranofin enhanced the therapeutic effectiveness of colistin in mouse peritoneal infection models. These results suggested that the combination of colistin and auranofin might be a potential alternative for the treatment of Col-R Gram-negative bacterial infections.

Highlights

Polymyxins are considered as last resort drugs for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria
The combination of colistin and auranofin resulted in the elimination of all three mcr gene positive isolates at 4 h, with no regrowth observed for K. pneumoniae C505 and K. pneumoniae 09-20
Colistin monotherapy could not prevent the growth of all high-level Col-R strains except K. pneumoniae 18605, wherein colistin monotherapy reduced the initial bacterial count slightly in the first 2 h, regrowth to the control value was observed at 24 h

Summary

Introduction

Polymyxins (including polymyxin B and colistin) are considered as last resort drugs for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Polymyxins act on the outer membrane of Gram-negative bacteria, disrupt the stability of cell membrane, cause osmotic imbalance, and lead to cell death (Velkov et al, 2010; Berglund et al, 2015). Before 2015, mutations in chromosomal genes, such as pmrAB, phoPQ, and mgrB, were considered as the main causes of high-level polymyxin resistance (Olaitan et al, 2014). The discovery of plasmid-encoded mcr-1 gene led to global reports of polymyxin resistance (Liu et al, 2016; Wang R. et al, 2018). The gradual emergence of the polymyxin-resistant bacterial strains has greatly limited the antibiotic therapy options. It has been shown that repurposing FDA-approved non-antibiotic drugs

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