The mechanism of resistance of the MCR gene is alipid A phosphoethanolamine transferase. The enzyme transfers a phosphoethanolamine residue to thelipid A present in thecell 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 likeeptA,[4]mcr-1 is the first polymyxin resistance gene known to be capable ofhorizontal transfer between different strains of a bacterial species.[1]
mcr-1 also provides resistance to hostantimicrobial peptides. Bacteria carrying the gene were better at killing infected caterpillars.[5]
The gene was first discovered inE. coli (strain SHP45) from apig inChina 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 aPennsylvania clinic forUTI symptoms.PCR of anE. coli isolate cultured from her urine revealed themcr-1 gene for the first time in theUnited States,[12] and theCDC 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] Theprevalence 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]
Using genetic analysis, researchers believe that they have shown that the origins of the gene were on a Chinese pig farm wherecolistin was routinely used.[16][17]
Given the importance ofmcr-1 in enabling bacteria to acquire polymyxin resistance, MCR-1 (the protein that is encoded bymcr-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 asethanolamine andglucose, 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 bymcr-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]
As of April 2021[update], ten mobilized colistin resistance genes termedmcr-1 throughmcr-10 have been identified. They arehomologous to each other, and work in similar ways.[24] Themcr-2 gene is a rare variant ofmcr-1 and is found only inBelgium. The less-relatedmcr-3,mcr-4, andmcr-5 were identified inE. coli andSalmonella.[25]
On thephylogenic tree, the various clusters ofmcr genes are scattered between immobile resistance genes of the same type, suggesting a history of multiple transfer to plasmids.[26][27][20][28]
^abcdLiu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J (February 2016). "Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study".The Lancet. Infectious Diseases.16 (2):161–8.doi:10.1016/S1473-3099(15)00424-7.PMID26603172.
^"Trackingmcr-1".Antibiotic/Antimicrobial Resistance: Biggest Threats. Centers for Disease Control and Prevention. 24 February 2017. Archived fromthe original on 17 January 2017. Retrieved10 January 2017.
^Nezhadi J, Narenji H, Barhaghi MH, Rezaee MA, Ghotaslou R, Pirzadeh T, Tanomand A, Ganbarov K, Bastami M, Madhi M, Yousefi M, Kafil HS (July 2022). "Peptide nucleic acid-mediated re-sensitization of colistin resistance Escherichia coli KP81 harboring mcr-1 plasmid".Microb. Pathog.135: 103646.doi:10.1016/j.micpath.2019.103646.PMID31344478.
^Wang X, Wang Y, Ling Z, Zhang C, Fu M, Wang Y, Wang S, Zhang S, Shen Z (August 2020). "Peptide nucleic acid restores colistin susceptibility through modulation of MCR-1 expression in Escherichia coli".J. Antimicrob. Chemother.75 (8):2059–2065.doi:10.1093/jac/dkaa140.PMID32417908.
^Hussein NH, AL-Kadmy IM, Taha BM, et al. (April 2021). "Mobilized colistin resistance (mcr) genes from 1 to 10: a comprehensive review".Mol Biol Rep.48 (3):2897–2907.doi:10.1007/s11033-021-06307-y.PMID33839987.S2CID233214659.
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