Novel Plasmid-Mediated Colistin Resistance Gene mcr-3 in Escherichia coli

Abstract

The mobile colistin resistance gene mcr-1 has attracted global attention, as it heralds the breach of polymyxins, one of the last-resort antibiotics for the treatment of severe clinical infections caused by multidrug-resistant Gram-negative bacteria. To date, six slightly different variants of mcr-1, and a second mobile colistin resistance gene, mcr-2, have been reported or annotated in the GenBank database. Here, we characterized a third mobile colistin resistance gene, mcr-3. The gene coexisted with 18 additional resistance determinants in the 261-kb IncHI2-type plasmid pWJ1 from porcine Escherichia coli. mcr-3 showed 45.0% and 47.0% nucleotide sequence identity to mcr-1 and mcr-2, respectively, while the deduced amino acid sequence of MCR-3 showed 99.8 to 100% and 75.6 to 94.8% identity to phosphoethanolamine transferases found in other Enterobacteriaceae species and in 10 Aeromonas species, respectively. pWJ1 was mobilized to an E. coli recipient by conjugation and contained a plasmid backbone similar to those of other mcr-1-carrying plasmids, such as pHNSHP45-2 from the original mcr-1-harboring E. coli strain. Moreover, a truncated transposon element, TnAs2, which was characterized only in Aeromonas salmonicida, was located upstream of mcr-3 in pWJ1. This ΔTnAs2-mcr-3 element was also identified in a shotgun genome sequence of a porcine E. coli isolate from Malaysia, a human Klebsiella pneumoniae isolate from Thailand, and a human Salmonella enterica serovar Typhimurium isolate from the United States. These results suggest the likelihood of a wide dissemination of the novel mobile colistin resistance gene mcr-3 among Enterobacteriaceae and aeromonads; the latter may act as a potential reservoir for mcr-3.

Molecular detection of colistin resistance genes (mcr-1, mcr-2 and mcr-3) in nasal/oropharyngeal and anal/cloacal swabs from pigs and poultry

“…coli in China 23 and later shown to be present in bacteria isolated from humans from Denmark, chickens from China, cattle from Spain 19,20,24–26 , and flies in China 31 . Our findings indicate that the gene is quite widespread, as we found it in samples from pigs and poultry from many provinces in China, albeit at low prevalence in some cases.…”

“…However, the usefulness of colistin as a last resort antimicrobial is now compromised by the presence of an increasing number of mobile colistin resistance genes ( mcr ). To date, five different mcr and their variants have been described, mainly mcr-1 (11 variants) 3–21 , mcr-2 (three variants) 11–18,21,22 , mcr-3 (ten variants) 19,20,23–26 , mcr-4 27 and mcr-5 28 . The mcr-1 , mcr-2 and mcr-3 were originally described on plasmids in Enterobacteriaceae but have recently been identified on the chromosomes of Moraxella spp.…”

Newly identified colistin resistance genes, mcr-4 and mcr-5, from upper and lower alimentary tract of pigs and poultry in China

“…The usefulness of colistin, the last-resort antibiotic used to treat multidrug resistant Gram-negative bacterial infections, is being compromised with the recent identification of the mobile colistin resistance gene, mcr-1 [3], and the subsequent finding of mcr-2 , mcr-3 , mcr-4 and mcr-5 [4–5, 23–26]. The mcr-1 , mcr-2 and mcr-3 have been detected in bacteria or swabs from a variety of hosts in China and elsewhere in the world [3–22] However, there are yet only few reports on mcr-4 and mcr-5 [23–26].…”

“…coli isolates from porcine of Belgium and in flies of China [4, 22]. After its first characterization on a IncHI2-type plasmid, pWJ1, from Escherichia coli isolated from a Chinese pig [5], the mcr -3 gene was shown to be present in bacteria isolated from humans in Denmark, chickens and flies in China, pigs in Japan and cattle in Spain [20–22, 26, 31]. …”

Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria

“…6 In June of 2016, the mcr-2 gene with ~76% identity to mcr-1 was identified in E. coli in Belgium, 7 and mcr-3 , having ~45% identity with mcr-1 , was recently reported from porcine E. coli strains in China. 8 The spread of colistin resistance coupled with the lack of new treatments for Gram-negative bacterial infections has created a situation in which contraction of an incurable, pan-resistant bacterial infection is a possibility. One such case was recently reported in Nevada, when a 70-year-old woman was infected with a Klebsiella pneumoniae strain resistant to all antibiotics clinically available in the US.…”