Biology:Plasmid-mediated resistance

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Short description: Antibiotic resistance caused by a plasmid
An example plasmid with two areas of antibiotic resistance coding DNA (1,2) and an origin of replication (3).

Plasmid-mediated resistance is the transfer of antibiotic resistance genes which are carried on plasmids.[1] Plasmids possess mechanisms that ensure their independent replication as well as those that regulate their replication number and guarantee stable inheritance during cell division. By the conjugation process, they can stimulate lateral transfer between bacteria from various genera and kingdoms.[2] Numerous plasmids contain addiction-inducing systems that are typically based on toxin-antitoxin factors and capable of killing daughter cells that don't inherit the plasmid during cell division.[3] Plasmids often carry multiple antibiotic resistance genes, contributing to the spread of multidrug-resistance (MDR).[4] Antibiotic resistance mediated by MDR plasmids severely limits the treatment options for the infections caused by Gram-negative bacteria, especially family Enterobacteriaceae.[5] The global spread of MDR plasmids has been enhanced by selective pressure from antimicrobial medications used in medical facilities and when raising animals for food.[6]

Properties of resistance plasmids

Resistance plasmids by definition carry one or more antibiotic resistance genes.[7] They are frequently accompanied by the genes encoding virulence determinants,[8] specific enzymes or resistance to toxic heavy metals.[9] Multiple resistance genes are commonly arranged in the resistance cassettes.[7] The antibiotic resistance genes found on the plasmids confer resistance to most of the antibiotic classes used nowadays, for example, beta-lactams, fluoroquinolones and aminoglycosides.[10]

It is very common for the resistance genes or entire resistance cassettes to be re-arranged on the same plasmid or be moved to a different plasmid or chromosome by means of recombination systems. Examples of such systems include integrons, transposons, and ISCR-promoted gene mobilization.[7]

Most of the resistance plasmids are conjugative, meaning that they encode all the needed components for the transfer of the plasmid to another bacterium,[11] and that isn't present in mobilizable plasmids. According to that, Mobilizable plasmids are smaller in size (usually < 10 kb) while conjugative plasmids are largger (usually > 30 kb) due to the considerable size of DNA required to encode the conjugation mechanisms that allow for cell-to-cell conjugation.[7]

R-factor

R-factors are also called a resistance factors or resistance plasmid. They are tiny, circular DNA elements that are self-replicating,[12] that contain antibiotic resistance genes.[13] They were first found in Japan in 1959 when it was discovered that some Shigella strains had developed resistance to a number of antibiotics used to treat a dysentery epidemic. Shigella is a genus of Gram-negative, aerobic, non-spore-forming, non-motile, rod-shaped bacteria.[12] Resistance genes are ones that give rise to proteins that modify the antibiotic or pump it out. They are different from mutations that give bacteria resistance to antibiotics by preventing the antibiotic from getting in or changing the shape of the target protein.[14] R-factors have been known to contain up to ten resistance genes. They can also spread easily as they contain genes for constructing pili, which allow them to transfer the R-factor to other bacteria.[15] R-factors have contributed to the growing antibiotic resistance crisis because they quickly spread resistance genes among bacteria.[16] The R factor by itself cannot be transmitted.[12]

Structure of Resistance Plasmids

The majority of the R-RTF (Resistance Transfer Factor) molecules are found in the resistance plasmid, which can be conceptualized as a circular piece of DNA with a length of 80 to 95 kb.[12] This plasmid shares many genes with the F factor and is largely homologous to it.[17] Additionally, it has a fin 0 gene that inhibits the transfer operon's functionality. The size and number of drug resistance genes in each R factor varies.The RTF is bigger than the R determinant. An IS 1 element separates the RTF and R determinant on either side before they combine into a single unit.The IS 1 components simplify it for R determinants to be transferred between different R-RTF unit types.[12]

Functions of Resistance Plasmids

  • they play a role in the autonomous replication, conjugation, and ampicillin resistance genes.[12]
  • Genes in the resistance plasmids enable bacteria to produce Pilli and develop resistance to antibiotics.[7]
  • MDR genes in bacteria are transmitted mainly through the resistance plasmids.[4]

Transmission

Bacteria containing F-factors (said to be "F+") have the capability for horizontal gene transfer; they can construct a sex pilus, which emerges from the donor bacterium and ensnares the recipient bacterium, draws it in,[18] and eventually triggers the formation of a mating bridge, merging the cytoplasms of two bacteria via a controlled pore.[19] This pore allows the transfer of genetic material, such as a plasmid. Conjugation allows two bacteria, not necessarily from the same species, to transfer genetic material one way.[20] Since many R-factors contain F-plasmids, antibiotic resistance can be easily spread among a population of bacteria.[21] Also, R-factors can be taken up by "DNA pumps" in their membranes via transformation,[22] or less commonly through viral mediated transduction,[23] or via bacteriophage, although conjugation is the most common means of antibiotic resistance spread. They contain the gene called RTF (Resistance transfer factor).

Enterobacteriaceae

Escherichia coli bacteria on the right are sensitive to two beta-lactam antibiotics, and do not grow in the semi-circular regions surrounding the antibiotics. E. coli bacteria on the left are resistant to beta-lactam antibiotics, and grow next to one antibiotic (bottom) and are less inhibited by another antibiotic (top).

it is a family of Gram-negative rod-shaped (bacilli) bacteria, the pathogenic bacteria that are most frequently found in the environment and clinical cases, as a result, they are significantly impacted by the use of antibiotics in agriculture, the ecosystem, or the treatment of diseases.[24] In Enterobacteriaceae, 28 different plasmid types can be identified by PCR-based replicon typing (PBRT).The plasmids that have been frequently reported [IncF, IncI, IncA/C, IncL (previously designated IncL/M), IncN, and IncH] contain a broad variety of resistance genes.[25]

Members of family Enterobacteriaceae, for example, Escherichia coli or Klebsiella pneumoniae pose the biggest threat regarding plasmid-mediated resistance in hospital- and community-acquired infections.[5]

Beta-lactam resistance

B-lactamases are antibiotic-hydrolyzing enzymes that typically cause resistance to b-lactam antibiotics. These enzymes are prevalent in Streptomyces, and together with related enzymes discovered in pathogenic and non-pathogenic bacteria, they form the protein family known as the "b-lactamase superfamily".[14] it is hypothesized that b-lactamases also serve a double purpose, such as housekeeping and antibiotic resistance.[26]

Both narrow spectrum beta-lactamases (e.g. penicillinases) and extended spectrum beta-lactamases (ESBL) are common for resistance plasmids in Enterobacteriaceae. Often multiple beta-lactamase genes are found on the same plasmid hydrolyzing a wide spectrum of beta-lactam antibiotics.[5]

Extended spectrum beta-lactamases (ESBL)

ESBL enzymes can hydrolyze all beta-lactam antibiotics, including cephalosporins, except for the carpabepenems. The first clinically observed ESBL enzymes were mutated versions of the narrow spectrum beta-lactamases, like TEM and SHV. Other ESBL enzymes originate outside of family Enterobacteriaceae, but have been spreading as well.[5]

In addition, since the plasmids that carry ESBL genes also commonly encode resistance determinants for many other antibiotics, ESBL strains are often resistant to many non-beta-lactam antibiotics as well,[27] leaving very few options for the treatment.

Carbapenemases

Carbapenemases represent type of ESBL which are able to hydrolyze carbapenem antibiotics that are considered as the last-resort treatment for ESBL-producing bacteria. KPC, NDM-1, VIM and OXA-48 carbapenemases have been increasingly reported worldwide as causes of hospital-acquired infections.[5]

Quinolone resistance

Several studies have shown that fluoroquinolone resistance has enhanced worldwide, especially in Enterobacteriaceae members. QnrA was the first known plasmid-mediated gene associated in quinolone resistance.[28]Quinolone resistance genes are frequently located on the same plasmid as the ESBL genes.[29] The proteins known as QnrS, QnrB, QnrC, and QnrD are four others that are similar. Numerous variants have been found for qnrA, qnrS, and qnrB, and they are distinguished by sequential numbers.[30] The qnr genes can be discovered in integrons and transposons on MDR plasmids of various incompatibility groups, which could carry a number of resistance-related molecules, such as carbapenemases and ESBLs.[31] Examples of resistance mechanisms include different Qnr proteins, aminoglycose acetyltransferase aac(6')-Ib-cr that is able to hydrolyze ciprofloxacin and norfloxacin, as well as efflux transporters OqxAB and QepA.[5]

Aminoglycoside resistance

xResistance to aminoglycosides in Gram-negative pathogens is primarily caused by enzymes that acetylate, adenylate, or phosphorylate the medication.[32] On mobile elements, such as plasmids, are the genes that encode these enzymes.[33]Aminoglycoside resistance genes are also commonly found together with ESBL genes. Resistance to aminoglycosides is conferred via numerous aminoglycoside-modifying enzymes and 16S rRNA methyltransferases.[5] Resistance to aminoglycosides is conferred via numerous mechanisms:

  1. aminoglycoside-modifying enzymes and inactivation of the aminoglycosides, which is frequently seen in both gram-positive and gram-negative bacteria and is induced by nucleotidyltransferases, phosphotransferases, or aminoglycoside acetyltransferases.
  2. reduced permeability.
  3. enhanced efflux.
  4. variations to the 30S ribosomal subunit that prevent aminoglycosides from binding to it.[34]

small RNAs

Study investigating physiological effect of pHK01 plasmid in host E.coli J53 found that the plasmid reduced bacterial motility and conferred resistance to beta-lactams. The pHK01 produced plasmid-encoded small RNAs and mediated expression of host sRNAs. These sRNAs were antisense to genes involved in replication, conjugate transfer and plasmid stabilisation : AS-repA3 (CopA), AS-traI, AS-finO, AS-traG, AS-pc02 . The over-expression of one of the plasmid-encoded antisense sRNAs: AS-traI shortened t lalog phase of host growth.[35]

References

  1. ↑ "Evolution of Plasmid-Mediated Antibiotic Resistance in the Clinical Context". Trends in Microbiology 26 (12): 978–985. December 2018. doi:10.1016/j.tim.2018.06.007. PMID 30049587. 
  2. ↑ "conjugation (prokaryotes) | Learn Science at Scitable" (in en). https://www.nature.com/scitable/definition/conjugation-prokaryotes-290/. 
  3. ↑ "Bacterial plasmid addiction systems and their implications for antibiotic drug development". Postdoc Journal 5 (5): 3–9. May 2017. PMID 28781980. 
  4. ↑ 4.0 4.1 "Multidrug resistance in bacteria". Annual Review of Biochemistry 78 (1): 119–146. 2009-06-01. doi:10.1146/annurev.biochem.78.082907.145923. PMID 19231985. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Plasmid-mediated resistance in Enterobacteriaceae: changing landscape and implications for therapy". Drugs 72 (1): 1–16. January 2012. doi:10.2165/11597960-000000000-00000. PMID 22191792. 
  6. ↑ "The role of epidemic resistance plasmids and international high-risk clones in the spread of multidrug-resistant Enterobacteriaceae". Clinical Microbiology Reviews 28 (3): 565–591. July 2015. doi:10.1128/CMR.00116-14. PMID 25926236. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Plasmid encoded antibiotic resistance: acquisition and transfer of antibiotic resistance genes in bacteria". British Journal of Pharmacology 153 (Suppl 1): S347–S357. March 2008. doi:10.1038/sj.bjp.0707607. PMID 18193080. 
  8. ↑ "Are Virulence and Antibiotic Resistance Genes Linked? A Comprehensive Analysis of Bacterial Chromosomes and Plasmids". Antibiotics 11 (6): 706. May 2022. doi:10.3390/antibiotics11060706. PMID 35740113. 
  9. ↑ "Plasmid Mediated Antibiotic and Heavy Metal Resistance in Bacillus Strains Isolated from Soils in Rize, Turkey". Suleyman Demirel University Journal of Natural and Applied Science 19 (2): 133–141. 2015. https://dergipark.org.tr/tr/download/article-file/194072. 
  10. ↑ "Antimicrobial Resistance Genes, Cassettes, and Plasmids Present in Salmonella enterica Associated With United States Food Animals". Frontiers in Microbiology 10: 832. 2019. doi:10.3389/fmicb.2019.00832. PMID 31057528. 
  11. ↑ "Control of genes for conjugative transfer of plasmids and other mobile elements". FEMS Microbiology Reviews 21 (4): 291–319. 1998. doi:10.1111/j.1574-6976.1998.tb00355.x. PMID 25481925. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 "R-Factor - Structure and Functions of Resistance Factors or Plasmids" (in en). https://byjus.com/biology/r-factor/. 
  13. ↑ "R-Factor". https://www.vedantu.com/biology/r-factor. 
  14. ↑ 14.0 14.1 "Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens". Frontiers in Microbiology 9: 2928. 2018. doi:10.3389/fmicb.2018.02928. PMID 30555448. 
  15. ↑ "The Spread of Antibiotic Resistance Genes In Vivo Model". The Canadian Journal of Infectious Diseases & Medical Microbiology 2022: 3348695. 2022-07-18. doi:10.1155/2022/3348695. PMID 35898691. 
  16. ↑ Biology A Global Approach (11th ed.). New York: Pearson. 2018. p. 633. ISBN 978-1-292-17043-5. 
  17. ↑ "Comparative Genomics of the Conjugation Region of F-like Plasmids: Five Shades of F". Frontiers in Molecular Biosciences 3: 71. 2016. doi:10.3389/fmolb.2016.00071. PMID 27891505. 
  18. ↑ "Protein Dynamics in F-like Bacterial Conjugation". Biomedicines 8 (9): 362. September 2020. doi:10.3390/biomedicines8090362. PMID 32961700. 
  19. ↑ "Plasmid Transfer by Conjugation in Gram-Negative Bacteria: From the Cellular to the Community Level". Genes 11 (11): 1239. October 2020. doi:10.3390/genes11111239. PMID 33105635. 
  20. ↑ "Prokaryotic Cell Structure: Pili". http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit1/prostruct/pili.html. 
  21. ↑ "A Brief History of Plasmids". EcoSal Plus 10 (1): eESP00282021. December 2022. doi:10.1128/ecosalplus.ESP-0028-2021. PMID 35373578. 
  22. ↑ "Membrane-associated DNA transport machines". Cold Spring Harbor Perspectives in Biology 2 (7): a000406. July 2010. doi:10.1101/cshperspect.a000406. PMID 20573715. 
  23. ↑ "Viral and nonviral delivery systems for gene delivery". Advanced Biomedical Research 1: 27. 2012. doi:10.4103/2277-9175.98152. PMID 23210086. 
  24. ↑ "Enterobacteriaceae- Definition, Characteristics, Identification" (in en-US). 2022-05-20. https://microbenotes.com/enterobacteriaceae/. 
  25. ↑ "Plasmids carrying antimicrobial resistance genes in Enterobacteriaceae". The Journal of Antimicrobial Chemotherapy 73 (5): 1121–1137. May 2018. doi:10.1093/jac/dkx488. PMID 29370371. 
  26. ↑ "Ecology and Evolution of Chromosomal Gene Transfer between Environmental Microorganisms and Pathogens". Microbiology Spectrum 6 (1): 6.1.06. January 2018. doi:10.1128/microbiolspec.MTBP-0006-2016. PMID 29350130. 
  27. ↑ "Broad spectrum antibiotics and resistance in non-target bacteria: an example from tetracycline". Journal of Pure and Applied Microbiology 8 (4): 2667–2671. 2014. 
  28. ↑ "Origin of plasmid-mediated quinolone resistance determinant QnrA". Antimicrobial Agents and Chemotherapy 49 (8): 3523–3525. August 2005. doi:10.1128/AAC.49.8.3523-3525.2005. PMID 16048974. 
  29. ↑ "Distribution of quinolone resistance gene (qnr) in ESBL-producing Escherichia coli and Klebsiella spp. in Lomé, Togo". Antimicrobial Resistance and Infection Control 8 (1): 104. 2019-06-18. doi:10.1186/s13756-019-0552-0. PMID 31244995. 
  30. ↑ "Plasmid-mediated fluoroquinolone resistance in clinical isolates of Escherichia coli in Konya, Turkey". Cukurova Medical Journal 43 (2): 295–300. 2018. doi:10.17826/cumj.341637. https://dergipark.org.tr/tr/download/article-file/465107. 
  31. ↑ "Plasmid-mediated quinolone resistance: a multifaceted threat". Clinical Microbiology Reviews 22 (4): 664–689. October 2009. doi:10.1128/CMR.00016-09. PMID 19822894. 
  32. ↑ "Amikacin: Uses, Resistance, and Prospects for Inhibition". Molecules 22 (12): 2267. December 2017. doi:10.3390/molecules22122267. PMID 29257114. 
  33. ↑ "Occurrence of aminoglycoside-modifying enzymes among isolates of Escherichia coli exhibiting high levels of aminoglycoside resistance isolated from Korean cattle farms". FEMS Microbiology Letters 364 (14). August 2017. doi:10.1093/femsle/fnx129. PMID 28637330. 
  34. ↑ "Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA Methyltransferases". Infectious Disease Clinics of North America. Antibiotic Resistance: Challenges and Opportunities 30 (2): 523–537. June 2016. doi:10.1016/j.idc.2016.02.011. PMID 27208771. 
  35. ↑ "The CTX-M-14 plasmid pHK01 encodes novel small RNAs and influences host growth and motility". FEMS Microbiology Ecology 93 (7). July 2017. doi:10.1093/femsec/fix090. PMID 28854680. 

Further reading




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