The mobilized colistin resistance (mcr) gene confers plasmid-mediated resistance to colistin, one of a number of last-resort antibiotics for treating Gram-negative infections. mcr-1, the original variant, is capable of horizontal transfer between different strains of a bacterial species. After discovery in November 2015 in E. coli (strain SHP45) from a pig in China it has been found in Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. As of 2017[update], it has been detected in more than 30 countries on 5 continents in less than a year.
| Probable phosphatidylethanolamine transferase Mcr-1 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Organism | |||||||
| Symbol | mcr1 | ||||||
| UniProt | A0A0R6L508 | ||||||
| |||||||
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Description
The "mobilized colistin resistance" (mcr-1) gene confers plasmid-mediated resistance to colistin, a polymyxin and one of a number of last-resort antibiotics for treating infections.[1][2] The gene is found in no less than ten species of the Enterobacteriaceae: Escherichia coli, Salmonella, Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae, Cronobacter sakazakii, Shigella sonnei, Kluyvera species, Citrobacter species, and Raoultella ornithinolytica.[citation needed]
The mechanism of resistance of the MCR gene is a lipid A phosphoethanolamine transferase. The enzyme transfers a phosphoethanolamine residue to the lipid A present in the cell membrane of gram-negative bacteria. The altered lipid A has much lower affinity for colistin and related polymyxins resulting in reduced activity of the antimicrobial. This type of resistance is known as target modification.[3] Although the same mechanism has been observed before with enzymes like eptA,[4] mcr-1 is the first polymyxin resistance gene known to be capable of horizontal transfer between different strains of a bacterial species.[1]
mcr-1 also provides resistance to host antimicrobial peptides. Bacteria carrying the gene were better at killing infected caterpillars.[5]
Discovery and geographical spread
The gene was first discovered in E. coli (strain SHP45) from a pig in China April 2011 and published in November 2015.[6][7] It was identified by independent researchers in human samples from Malaysia, China,[1] England,[8][9] Scotland,[10] and the United States.[11]
In April 2016, a 49-year-old woman sought medical care at a Pennsylvania clinic for UTI symptoms. PCR of an E. coli isolate cultured from her urine revealed the mcr-1 gene for the first time in the United States,[12] and the CDC sent an alert to health care facilities. In the following twelve months, four additional people were reported to have infections with mcr-1 carrying bacteria.[13]
As of February 2017[update] mcr-1 has been detected in more than 30 countries on 5 continents in less than a year,[14] and it appears to be spreading in hospitals in China.[15] The prevalence in five Chinese provinces between April 2011 and November 2014 was 15% in raw meat samples and 21% in food animals during 2011–14, and 1% in people hospitalized with infection.[1]
Origins
Using genetic analysis, researchers believe that they have shown that the origins of the gene were on a Chinese pig farm where colistin was routinely used.[16][17]
Inhibition
Given the importance of mcr-1 in enabling bacteria to acquire polymyxin resistance, MCR-1 (the protein that is encoded by mcr-1) is a current inhibition target for the development of new antibiotic adjuvants.[18][19] For example, ethylenediaminetetraacetic acid (EDTA), a metal-chelating agent and common food additive, was shown to inhibit MCR-1 as it is a zinc-dependent enzyme.[3] Substrate analogues, such as ethanolamine and glucose, were also shown to inhibit MCR-1.[20] The use of a combined antibiotics regime has shown to be able to overcome the resistance that is caused by mcr-1, and the mechanism of action may be directly or indirectly targeting the MCR-1 protein.[21] Recently, a couple of studies showed that peptide nucleic acids (PNAs), a class of antisense molecules, when conjugated with cell-penetrating peptides, may inhibit the translation of MCR to turn off polymyxin resistance.[22][23]
Other mcr genes
As of April 2021[update], ten mobilized colistin resistance genes termed mcr-1 through mcr-10 have been identified. They are homologous to each other, and work in similar ways.[24] The mcr-2 gene is a rare variant of mcr-1 and is found only in Belgium. The less-related mcr-3, mcr-4, and mcr-5 were identified in E. coli and Salmonella.[25]
On the phylogenic tree, the various clusters of mcr genes are scattered between immobile resistance genes of the same type, suggesting a history of multiple transfer to plasmids.[26][27][20][28]
See also
References
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