Biology:MCR-1

From HandWiki
Probable phosphoethanolamine transferase Mcr-1
Identifiers
OrganismEscherichia coli
Symbolmcr1
UniProtA0A0R6L508
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

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 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, 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

  1. ↑ 1.0 1.1 1.2 1.3 "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. February 2016. doi:10.1016/S1473-3099(15)00424-7. PMID 26603172. 
  2. ↑ Reardon, Sara (21 December 2015). "Spread of antibiotic-resistance gene does not spell bacterial apocalypse — yet". Nature. doi:10.1038/nature.2015.19037. http://www.nature.com/news/spread-of-antibiotic-resistance-gene-does-not-spell-bacterial-apocalypse-yet-1.19037. 
  3. ↑ 3.0 3.1 "Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1". Scientific Reports 7: 39392. January 2017. doi:10.1038/srep39392. PMID 28059088. Bibcode: 2017NatSR...739392H. 
  4. ↑ "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. February 2017. doi:10.1073/pnas.1612927114. PMID 28193899. Bibcode: 2017PNAS..114.2218A. 
  5. ↑ Jangir, Pramod K; Ogunlana, Lois; Szili, Petra; Czikkely, Marton; Shaw, Liam P; Stevens, Emily J; Yang, Yu; Yang, Qiue et al. (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. 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. https://www.cdc.gov/drugresistance/mcr1.html. 
  7. ↑ "Dissemination and Mechanism for the MCR-1 Colistin Resistance". PLOS Pathogens 12 (11): e1005957. November 2016. doi:10.1371/journal.ppat.1005957. PMID 27893854. 
  8. ↑ Schnirring, Lisa (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. http://www.cidrap.umn.edu/news-perspective/2015/12/more-mcr-1-findings-lead-calls-ban-ag-use-colistin. 
  9. ↑ McKenna, Maryn (3 December 2015). "Apocalypse Pig Redux: Last-Resort Resistance in Europe". Phenomena. http://phenomena.nationalgeographic.com/2015/12/03/colistin-r-2/. 
  10. ↑ "Antibiotic-resistant bacteria detected in Scotland" (in en-GB). BBC News. 2016-08-03. https://www.bbc.co.uk/news/uk-scotland-36962781. 
  11. ↑ The U.S. Military HIV Research Program (MHRP). "First discovery in United States of colistin resistance in a human E. coli infection". ScienceDaily. https://www.sciencedaily.com/releases/2016/05/160526152033.htm. 
  12. ↑ Wappes, Jim (26 May 2016). "Highly resistant MCR-1 'superbug' found in US for first time". CIDRAP News. CIDRAP — Center for Infectious Disease Research and Policy. http://www.cidrap.umn.edu/news-perspective/2016/05/highly-resistant-mcr-1-superbug-found-us-first-time. 
  13. ↑ "Tracking mcr-1". Antibiotic/Antimicrobial Resistance: Biggest Threats. Centers for Disease Control and Prevention. 24 February 2017. https://www.cdc.gov/drugresistance/tracking-mcr1.html. 
  14. ↑ "mcr-1-Harboring Salmonella enterica Serovar Typhimurium Sequence Type 34 in Pigs, China". Emerging Infectious Diseases 23 (2): 291–295. February 2017. doi:10.3201/eid2302.161543. PMID 28098547. 
  15. ↑ Dall, Chris (27 January 2017). "Studies show spread of MCR-1 gene in China". CIDRAP News. CIDRAP — Center for Infectious Disease Research and Policy. http://www.cidrap.umn.edu/news-perspective/2017/01/studies-show-spread-mcr-1-gene-china. 
  16. ↑ Nield, David. "A Dangerous Antibiotic-Resistant Gene Has Spread The World. We Now Know Where It Started" (in en-gb). ScienceAlert. https://www.sciencealert.com/antibiotic-resistant-mcr-1-gene-spreads-worldwide-from-chinese-pig-farms. 
  17. ↑ "The global distribution and spread of the mobilized colistin resistance gene mcr-1" (in En). Nature Communications 9 (1): 1179. March 2018. doi:10.1038/s41467-018-03205-z. PMID 29563494. Bibcode: 2018NatCo...9.1179W. 
  18. ↑ "MCR-1: a promising target for structure-based design of inhibitors to tackle polymyxin resistance". Drug Discovery Today 24 (1): 206–216. January 2019. doi:10.1016/j.drudis.2018.07.004. PMID 30036574. 
  19. ↑ "Adjuvant strategies to tackle mcr-mediated polymyxin resistance". RSC Medicinal Chemistry. November 2024. doi:10.1039/D4MD00654B. PMID 39539347. 
  20. ↑ 20.0 20.1 "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. February 2018. doi:10.1096/fj.201700705R. PMID 29079699. 
  21. ↑ "Re-sensitization of mcr carrying multidrug resistant bacteria to colistin by silver". Proc Natl Acad Sci U S A 119 (11): e2119417119. March 2022. doi:10.1073/pnas.2119417119. PMID 35263219. Bibcode: 2022PNAS..11919417Z. 
  22. ↑ "Peptide nucleic acid-mediated re-sensitization of colistin resistance Escherichia coli KP81 harboring mcr-1 plasmid". Microb. Pathog. 135: 103646. July 2022. doi:10.1016/j.micpath.2019.103646. PMID 31344478. 
  23. ↑ "Peptide nucleic acid restores colistin susceptibility through modulation of MCR-1 expression in Escherichia coli". J. Antimicrob. Chemother. 75 (8): 2059–2065. August 2020. doi:10.1093/jac/dkaa140. PMID 32417908. 
  24. ↑ "Mobilized colistin resistance (mcr) genes from 1 to 10: a comprehensive review". Mol Biol Rep 48 (3): 2897–2907. April 2021. doi:10.1007/s11033-021-06307-y. PMID 33839987. 
  25. ↑ "Towards Understanding MCR-like Colistin Resistance". Trends in Microbiology 26 (9): 794–808. September 2018. doi:10.1016/j.tim.2018.02.006. PMID 29525421. 
  26. ↑ "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. May 2019. doi:10.1128/mBio.00853-19. PMID 31064835. 
  27. ↑ "An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance". mBio 9 (2). April 2018. doi:10.1128/mBio.02317-17. PMID 29636432. 
  28. ↑ Cuadrat, Rafael R C; Sorokina, Maria; Andrade, Bruno G; Goris, Tobias; Dávila, Alberto M R (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. PMID 32391909. PMC 7213576. https://doi.org/10.1093/gigascience/giaa046. 



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