mcr-1-Mediated In Vitro Inhibition of Plasmid Transfer Is Reversed by the Intestinal Environment

Abstract

Colistin is regarded as an antibiotic of last resort against multidrug-resistant Gram-negative bacteria, including Klebsiella pneumoniae and Escherichia coli. Colistin resistance is acquired by microorganisms via chromosome-mediated mutations or plasmid-mediated mobile colistin resistance (mcr) gene, in which the transfer of mcr is the predominant factor underlying the spread of colistin resistance. However, the factors that are responsible for the spread of the mcr gene are still unclear. In this study, we observed that mcr-1 inhibited the transfer of the pHNSHP45 backbone in liquid mating. Similar inhibitory effect of mcr-1.6 and chromosomal mutant ΔmgrB suggested that colistin resistance, acquired from either plasmid or chromosomal mutation, hindered the transfer of colistin resistance-related plasmid in vitro. Dual plasmid system further proved that co-existing plasmid transfer was reduced too. However, this inhibitory effect was reversed in vivo. Some factors in the gut, including bile salt and anaerobic conditions, could increase the transfer frequency of the mcr-1-containing plasmid. Our results demonstrated the potential risk for the spread of colistin resistance in the intestine, provide a scientific basis against the transmission of colistin resistance threat.

Factors and Mechanisms Influencing Conjugation In Vivo in the Gastrointestinal Tract Environment: A Review

“…Studies have shown that colistin resistance hinders plasmid conjugation related to colistin resistance in vitro. However, this phenomenon was reversed in the digestive tract of mice, as bile salts and anaerobic conditions in the intestine had a positive effect on the conjugation of the mcr- 1 plasmid [ 33 ]. In addition, bile is an amphiphilic detergent molecule [ 51 ], which can cause damage to the bacterial cell membrane and increase the permeability of the bacterial cell membrane, which is conducive to conjugative transfer.…”

“…Hence, it is necessary to identify the factors and mechanisms affecting conjugation in vivo and develop inhibitory strategies based on these factors to prevent the spread of ARGs. In fact, there have been numerous reports about the effects of substances on in vivo conjugation [ 32 , 33 , 34 ]. Logan C Ott et al summarized the research model of conjugative transfer from computer simulation in vitro and in vivo, which reflected the real situation in the intestine and laid a foundation for further research on the factors and mechanisms affecting intestinal conjugation [ 35 ].…”