Plasmid-mediated resistance is the transfer of
antibiotic resistance
Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
genes which are carried on
plasmid
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
s. 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
Conjugation or conjugate may refer to:
Linguistics
* Grammatical conjugation, the modification of a verb from its basic form
* Emotive conjugation or Russell's conjugation, the use of loaded language
Mathematics
* Complex conjugation, the chang ...
process, they can stimulate lateral transfer between bacteria from various genera and kingdoms. 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. Plasmids often carry multiple
antibiotic resistance
Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
genes, contributing to the spread of
multidrug-resistance
Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are c ...
(MDR).
Antibiotic resistance mediated by MDR plasmids severely limits the treatment options for the infections caused by
Gram-negative bacteria
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
, especially family
Enterobacteriaceae
Enterobacteriaceae is a large family (biology), family of Gram-negative bacteria. It was first proposed by Rahn in 1936, and now includes over 30 genera and more than 100 species. Its classification above the level of family is still a subject ...
.
The global spread of MDR plasmids has been enhanced by
selective pressure
Any cause that reduces or increases reproductive success in a portion of a population potentially exerts evolutionary pressure, selective pressure or selection pressure, driving natural selection. It is a quantitative description of the amount of ...
from antimicrobial medications used in medical facilities and when raising animals for food.
Properties of resistance plasmids
Resistance plasmids by definition carry one or more antibiotic resistance genes.
They are frequently accompanied by the genes encoding
virulence
Virulence is a pathogen's or microorganism's ability to cause damage to a host.
In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ca ...
determinants, specific enzymes or resistance to toxic
heavy metals
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Heavy metals are generally defined as ...
. Multiple resistance genes are commonly arranged in the resistance cassettes.
The antibiotic resistance genes found on the plasmids confer resistance to most of the antibiotic classes used nowadays, for example,
beta-lactams
A beta-lactam (β-lactam) ring is a four-membered lactam. A ''lactam'' is a cyclic amide, and ''beta''-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is ...
,
fluoroquinolones
A quinolone antibiotic is a member of a large group of broad-spectrum antibiotic, broad-spectrum bacteriocidals that share a bicyclic molecule, bicyclic core structure related to the substance 4-Quinolone, 4-quinolone. They are used in human and ...
and
aminoglycoside
Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...
s.
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
integron Integrons are genetic mechanisms that allow bacteria to adapt and evolve rapidly through the stockpiling and expression of new genes. These genes are embedded in a specific genetic structure called gene cassette (a term that is lately changing to in ...
s,
transposons
A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transpo ...
, and IS''CR''-promoted gene mobilization.
Most of the resistance plasmids are conjugative, meaning that they encode all the needed components for the transfer of the plasmid to another bacterium,
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.
R-factor
R-factors are also called a resistance factors or resistance plasmid,They are tiny, circular DNA elements that are self-replication,
that contain
antibiotic resistance
Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
genes. 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.
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.
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. R-factors have contributed to the growing antibiotic resistance crisis because they quickly spread resistance genes among bacteria. The R factor by itself cannot be transmitted.
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.
This plasmid shares many genes with the F factor and is largely homologous to it. 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.
Functions of Resistance Plasmids
* they play a role in the autonomous replication, conjugation, and ampicillin resistance genes.
* Genes in the resistance plasmids enable bacteria to produce Pilli and develop resistance to antibiotics.
* MDR genes in bacteria are transmitted mainly through the resistance plasmids.
Transmission
Bacteria containing F-factors (said to be "F+") have the capability for
horizontal gene transfer
Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between Unicellular organism, unicellular and/or multicellular organisms other than by the ("vertical") transmission of DNA from parent to offsprin ...
; they can construct a sex
pilus
A pilus (Latin for 'hair'; plural: ''pili'') is a hair-like appendage found on the surface of many bacteria and archaea. The terms ''pilus'' and '' fimbria'' (Latin for 'fringe'; plural: ''fimbriae'') can be used interchangeably, although some r ...
, which emerges from the donor bacterium and ensnares the recipient bacterium, draws it in, and eventually triggers the formation of a mating bridge, merging the cytoplasms of two bacteria via a controlled pore. This pore allows the transfer of genetic material, such as a
plasmid
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
. Conjugation allows two
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
, not necessarily from the same
species
In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate s ...
, to transfer genetic material one way. Since many R-factors contain F-plasmids, antibiotic resistance can be easily spread among a population of
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
. Also, R-factors can be taken up by "DNA pumps" in their membranes via
transformation
Transformation may refer to:
Science and mathematics
In biology and medicine
* Metamorphosis, the biological process of changing physical form after birth or hatching
* Malignant transformation, the process of cells becoming cancerous
* Trans ...
, or less commonly through viral mediated
transduction, or via bacteriophage, although conjugation is the most common means of antibiotic resistance spread. They contain the gene called RTF (Resistance transfer factor).
''Enterobacteriaceae''
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. In Enterobacteriaceae, 28 different plasmid types can be identified by PCR-based replicon typing (PBRT).The plasmids that have been frequently reported
ncF, IncI, IncA/C, IncL (previously designated IncL/M), IncN, and IncHcontain a broad variety of resistance genes.
Members of family Enterobacteriaceae, for example, ''
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' or ''
Klebsiella pneumoniae
''Klebsiella pneumoniae'' is a Gram-negative, non-motile, encapsulated, lactose-fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar.
Although found in the normal flora of the mouth ...
'' pose the biggest threat regarding plasmid-mediated resistance in hospital- and community-acquired infections.
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".
it is hypothesized that b-lactamases also serve a double purpose, such as housekeeping and antibiotic resistance.
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.
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.
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, 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 infection
A hospital-acquired infection, also known as a nosocomial infection (from the Greek , meaning "hospital"), is an infection that is acquired in a hospital or other health care facility. To emphasize both hospital and nonhospital settings, it is so ...
s.
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.
Quinolone
Quinolone may refer to:
* 2-Quinolone
* 4-Quinolone
* Quinolone antibiotic
A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They ...
resistance genes are frequently located on the same plasmid as the ESBL genes. 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. 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. Examples of resistance mechanisms include different Qnr proteins, aminoglycose acetyltransferase aac(6')-Ib-cr that is able to hydrolyze
ciprofloxacin
Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin infec ...
and
norfloxacin
Norfloxacin, sold under the brand name Noroxin among others, is an antibiotic that belongs to the class of fluoroquinolone antibiotics. It is used to treat urinary tract infections, gynecological infections, inflammation of the prostate gland, go ...
, as well as efflux transporters OqxAB and QepA.
Aminoglycoside resistance
xResistance to aminoglycosides in Gram-negative pathogens is primarily caused by enzymes that acetylate, adenylate, or phosphorylate the medication. On mobile elements, such as plasmids, are the genes that encode these enzymes.
Aminoglycoside
Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...
resistance genes are also commonly found together with ESBL genes. Resistance to aminoglycosides is conferred via numerous aminoglycoside-modifying enzymes and 16S rRNA methyltransferases.
Resistance to aminoglycosides is conferred via numerous mechanisms:
# 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.
# reduced permeability.
# enhanced efflux.
# variations to the 30S ribosomal subunit that prevent aminoglycosides from binding to it.
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 RNA
Small RNA (sRNA) are polymeric RNA molecules that are less than 200 nucleotides in length, and are usually non-coding
Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA ...
s 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.
References
Further reading
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{{DEFAULTSORT:Plasmid-Mediated Resistance
Plasmids
Cell biology