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MCR-1

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This article is about the antibiotic resistance mechanism. For the yeast gene, see Mcr1.
Probable phosphatidylethanolamine transferase Mcr-1
Identifiers
OrganismEscherichia coli
Symbolmcr1
UniProtA0A0R6L508
Search for
StructuresSwiss-model
DomainsInterPro
E. coli, the bacterium in which MCR-1 was first identified.

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, it has been detected in more than 30 countries on 5 continents in less than a year.

Description

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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

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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 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

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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

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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

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As of April 2021, 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

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References

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  1. ^ a b c d Liu 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. PMID 26603172.
  2. ^ Reardon S (21 December 2015). "Spread of antibiotic-resistance gene does not spell bacterial apocalypse — yet". Nature. doi:10.1038/nature.2015.19037. S2CID 182042290.
  3. ^ a b Hinchliffe P, Yang QE, Portal E, Young T, Li H, Tooke CL, Carvalho MJ, Paterson NG, Brem J, Niumsup PR, Tansawai U, Lei L, Li M, Shen Z, Wang Y, Schofield CJ, Mulholland AJ, Shen J, Fey N, Walsh TR, Spencer J (January 2017). "Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1". Scientific Reports. 7: 39392. Bibcode:2017NatSR...739392H. doi:10.1038/srep39392. PMC 5216409. PMID 28059088.
  4. ^ Anandan A, Evans GL, Condic-Jurkic K, O'Mara ML, John CM, Phillips NJ, Jarvis GA, Wills SS, Stubbs KA, Moraes I, Kahler CM, Vrielink A (February 2017). "Structure of a lipid A phosphoethanolamine transferase suggests how conformational changes govern substrate binding". Proceedings of the National Academy of Sciences of the United States of America. 114 (9): 2218–2223. Bibcode:2017PNAS..114.2218A. doi:10.1073/pnas.1612927114. PMC 5338521. PMID 28193899.
  5. ^ Jangir PK, Ogunlana L, Szili P, Czikkely M, Shaw LP, Stevens EJ, Yang Y, Yang Q, Wang Y, Pál C, Walsh TR, MacLean CR (25 April 2023). "The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence". eLife. 12: e84395. doi:10.7554/eLife.84395. PMC 10129329. PMID 37094804.
  6. ^ "Newly Reported Gene, mcr-1, Threatens Last-Resort Antibiotics". Antibiotic/Antimicrobial Resistance: AR Solutions in Action. Centers for Disease Control and Prevention. 30 November 2016.
  7. ^ Gao R, Hu Y, Li Z, Sun J, Wang Q, Lin J, Ye H, Liu F, Srinivas S, Li D, Zhu B, Liu YH, Tian GB, Feng Y (November 2016). "Dissemination and Mechanism for the MCR-1 Colistin Resistance". PLOS Pathogens. 12 (11): e1005957. doi:10.1371/journal.ppat.1005957. PMC 5125707. PMID 27893854.
  8. ^ Schnirring L (18 December 2015). "More MCR-1 findings lead to calls to ban ag use of colistin". CIDRAP News. CIDRAP — Center for Infectious Disease Research and Policy. Retrieved 2015-12-22.
  9. ^ McKenna M (3 December 2015). "Apocalypse Pig Redux: Last-Resort Resistance in Europe". Phenomena. Archived from the original on December 8, 2015. Retrieved 28 May 2016.
  10. ^ "Antibiotic-resistant bacteria detected in Scotland". BBC News. 2016-08-03. Retrieved 2017-03-29.
  11. ^ The U.S. Military HIV Research Program (MHRP). "First discovery in United States of colistin resistance in a human E. coli infection". ScienceDaily. Retrieved 2016-05-27.
  12. ^ Wappes J (26 May 2016). "Highly resistant MCR-1 'superbug' found in US for first time". CIDRAP News. CIDRAP — Center for Infectious Disease Research and Policy. Retrieved 2016-08-09.
  13. ^ "Tracking mcr-1". Antibiotic/Antimicrobial Resistance: Biggest Threats. Centers for Disease Control and Prevention. 24 February 2017. Archived from the original on 17 January 2017. Retrieved 10 January 2017.
  14. ^ Yi L, Wang J, Gao Y, Liu Y, Doi Y, Wu R, Zeng Z, Liang Z, Liu JH (February 2017). "mcr-1-Harboring Salmonella enterica Serovar Typhimurium Sequence Type 34 in Pigs, China". Emerging Infectious Diseases. 23 (2): 291–295. doi:10.3201/eid2302.161543. PMC 5324782. PMID 28098547.
  15. ^ Dall C (27 January 2017). "Studies show spread of MCR-1 gene in China". CIDRAP News. CIDRAP — Center for Infectious Disease Research and Policy.
  16. ^ Nield D. "A Dangerous Antibiotic-Resistant Gene Has Spread The World. We Now Know Where It Started". ScienceAlert. Retrieved 2018-04-02.
  17. ^ Wang R, van Dorp L, Shaw LP, Bradley P, Wang Q, Wang X, Jin L, Zhang Q, Liu Y, Rieux A, Dorai-Schneiders T, Weinert LA, Iqbal Z, Didelot X, Wang H, Balloux F (March 2018). "The global distribution and spread of the mobilized colistin resistance gene mcr-1". Nature Communications. 9 (1): 1179. Bibcode:2018NatCo...9.1179W. doi:10.1038/s41467-018-03205-z. PMC 5862964. PMID 29563494.
  18. ^ Son SJ, Huang R, Squire CJ, Leung IK (January 2019). "MCR-1: a promising target for structure-based design of inhibitors to tackle polymyxin resistance". Drug Discovery Today. 24 (1): 206–216. doi:10.1016/j.drudis.2018.07.004. hdl:2292/44893. PMID 30036574.
  19. ^ Nuske MR, Zhong J, Huang R, Sarojini V, Squire CJ, Blaskovich MA, Leung IK (November 2024). "Adjuvant strategies to tackle mcr-mediated polymyxin resistance". RSC Medicinal Chemistry. doi:10.1039/D4MD00654B. PMC 11556429. PMID 39539347.
  20. ^ a b Wei P, Song G, Shi M, Zhou Y, Liu Y, Lei J, Chen P, Yin L (February 2018). "Substrate analog interaction with MCR-1 offers insight into the rising threat of the plasmid-mediated transferable colistin resistance". FASEB Journal. 32 (2): 1085–1098. doi:10.1096/fj.201700705R. PMID 29079699.
  21. ^ Zhang Q, Wang RW, Wang MJ, Liu CJ, Moghadam, Wang HB, Ho PL, Li HY, Sun HZ (March 2022). "Re-sensitization of mcr carrying multidrug resistant bacteria to colistin by silver". Proc Natl Acad Sci U S A. 119 (11): e2119417119. Bibcode:2022PNAS..11919417Z. doi:10.1073/pnas.2119417119. PMC 8931383. PMID 35263219.
  22. ^ 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. PMID 31344478.
  23. ^ 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. PMID 32417908.
  24. ^ 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. PMID 33839987. S2CID 233214659.
  25. ^ Sun J, Zhang H, Liu YH, Feng Y (September 2018). "Towards Understanding MCR-like Colistin Resistance". Trends in Microbiology. 26 (9): 794–808. doi:10.1016/j.tim.2018.02.006. PMID 29525421. S2CID 3865269.
  26. ^ Carroll LM, Gaballa A, Guldimann C, Sullivan G, Henderson LO, Wiedmann M (May 2019). "Identification of Novel Mobilized Colistin Resistance Gene mcr-9 in a Multidrug-Resistant, Colistin-Susceptible Salmonella enterica Serotype Typhimurium Isolate". mBio. 10 (3): e00853–19. doi:10.1128/mBio.00853-19. PMC 6509194. PMID 31064835.
  27. ^ Xu Y, Wei W, Lei S, Lin J, Srinivas S, Feng Y (April 2018). "An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance". mBio. 9 (2). doi:10.1128/mBio.02317-17. PMC 5893884. PMID 29636432.
  28. ^ Cuadrat RR, Sorokina M, Andrade BG, Goris T, Dávila AM (2020-05-01). "Global ocean resistome revealed: Exploring antibiotic resistance gene abundance and distribution in TARA Oceans samples". GigaScience. 9 (5). doi:10.1093/gigascience/giaa046. ISSN 2047-217X. PMC 7213576. PMID 32391909.
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