Plasmid-mediated resistance

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An example plasmid with two areas of antibiotic resistance coding DNA (1,2) and an origin of replication (3). Example plasmid.svg
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]

Contents

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, that contain antibiotic resistance genes.[ citation needed ] 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.[ citation needed ] 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. [12] 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. [13] R-factors have contributed to the growing antibiotic resistance crisis because they quickly spread resistance genes among bacteria. [14] The R factor by itself cannot be transmitted.[ citation needed ]

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.[ citation needed ] This plasmid shares many genes with the F factor and is largely homologous to it. [15] 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.[ citation needed ]

Functions of Resistance Plasmids

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, [16] and eventually triggers the formation of a mating bridge, merging the cytoplasms of two bacteria via a controlled pore. [17] 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. [18] Since many R-factors contain F-plasmids, antibiotic resistance can be easily spread among a population of bacteria. [19] Also, R-factors can be taken up by "DNA pumps" in their membranes via transformation, [20] or less commonly through viral mediated transduction, [21] 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). ESBL Stokes.jpg
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. [22] 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. [23]

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". [12] it is hypothesized that b-lactamases also serve a double purpose, such as housekeeping and antibiotic resistance. [24]

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, [25] 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. [26] Quinolone resistance genes are frequently located on the same plasmid as the ESBL genes. [27] 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. [28] 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. [29] 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. [30] On mobile elements, such as plasmids, are the genes that encode these enzymes. [31] 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. [32]

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. [33]

Related Research Articles

<span class="mw-page-title-main">Beta-lactamase</span> Class of enzymes

Beta-lactamases (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam (β-lactam) ring. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.

<span class="mw-page-title-main">Beta-lactam antibiotics</span> Class of broad-spectrum antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

<span class="mw-page-title-main">Drug resistance</span> Pathogen resistance to medications

Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.

<span class="mw-page-title-main">Methicillin</span> Antibiotic medication

Methicillin (USAN), also known as meticillin (INN), is a narrow-spectrum β-lactam antibiotic of the penicillin class.

<i>Klebsiella pneumoniae</i> Species of bacterium

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.

<span class="mw-page-title-main">Clavulanic acid</span> Molecule used to overcome antibiotic resistance in bacteria

Clavulanic acid is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins.

<span class="mw-page-title-main">Piperacillin</span> Antibiotic medication

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

<i>Pseudomonas aeruginosa</i> Species of bacterium

Pseudomonas aeruginosa is a common encapsulated, Gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with serious illnesses – hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes. P. aeruginosa is able to selectively inhibit various antibiotics from penetrating its outer membrane - and has high resistance to several antibiotics, according to the World Health Organization P. aeruginosa poses one of the greatest threats to humans in terms of antibiotic resistance.

<span class="mw-page-title-main">Carbapenem</span> Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta-lactam antibiotics drug class, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

<i>Acinetobacter baumannii</i> Species of bacterium

Acinetobacter baumannii is a typically short, almost round, rod-shaped (coccobacillus) Gram-negative bacterium. It is named after the bacteriologist Paul Baumann. It can be an opportunistic pathogen in humans, affecting people with compromised immune systems, and is becoming increasingly important as a hospital-derived (nosocomial) infection. While other species of the genus Acinetobacter are often found in soil samples, it is almost exclusively isolated from hospital environments. Although occasionally it has been found in environmental soil and water samples, its natural habitat is still not known.

Capnocytophaga is a genus of Gram-negative bacteria. Normally found in the oropharyngeal tract of mammals, they are involved in the pathogenesis of some animal bite wounds and periodontal diseases.

β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

An origin of transfer (oriT) is a short sequence ranging from 40-500 base pairs in length that is necessary for the transfer of DNA from a gram-negative bacterial donor to recipient during bacterial conjugation. The transfer of DNA is a critical component for antimicrobial resistance within bacterial cells and the oriT structure and mechanism within plasmid DNA is complementary to its function in bacterial conjugation. The first oriT to be identified and cloned was on the RK2 (IncP) conjugative plasmid, which was done by Guiney and Helinski in 1979.

<span class="mw-page-title-main">New Delhi metallo-beta-lactamase 1</span> Enzyme

NDM-1 is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections. The gene for NDM-1 is one member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. Bacteria that produce carbapenemases are often referred to in the news media as "superbugs" because infections caused by them are difficult to treat. Such bacteria are usually sensitive only to polymyxins and tigecycline.

<span class="mw-page-title-main">Antibiotic resistance in gonorrhea</span>

Neisseria gonorrhoeae, the bacterium that causes the sexually transmitted infection gonorrhea, has developed antibiotic resistance to many antibiotics. The bacteria was first identified in 1879.

Carbapenem-resistant Enterobacteriaceae (CRE) or carbapenemase-producing Enterobacteriaceae (CPE) are Gram-negative bacteria that are resistant to the carbapenem class of antibiotics, considered the drugs of last resort for such infections. They are resistant because they produce an enzyme called a carbapenemase that disables the drug molecule. The resistance can vary from moderate to severe. Enterobacteriaceae are common commensals and infectious agents. Experts fear CRE as the new "superbug". The bacteria can kill up to half of patients who get bloodstream infections. Tom Frieden, former head of the Centers for Disease Control and Prevention has referred to CRE as "nightmare bacteria". Examples of enzymes found in certain types of CRE are KPC and NDM. KPC and NDM are enzymes that break down carbapenems and make them ineffective. Both of these enzymes, as well as the enzyme VIM have also been reported in Pseudomonas.

Nitrocefin Chemical compound

Nitrocefin is a chromogenic cephalosporin substrate routinely used to detect the presence of beta-lactamase enzymes produced by various microbes. Beta-lactamase mediated resistance to beta-lactam antibiotics such as penicillin is a widespread mechanism of resistance for a number of bacteria including members of the family Enterobacteriaceae, a major group of enteric Gram-negative bacteria. Other methods for beta-lactamase detection exist including PCR; however, nitrocefin allows for rapid beta-lactamase detection using few materials and inexpensive equipment.

<span class="mw-page-title-main">Ceftolozane/tazobactam</span> Antibiotic

Ceftolozane/tazobactam, sold under the brand name Zerbaxa, is a fixed-dose combination antibiotic medication used for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

Kluyvera is a Gram negative, facultatively anaerobic bacterial and motile genus from the family of Enterobacteriaceae which have peritrichous flagella. Kluyvera occur in water, soil and sewage. Kluyvera bacteria can cause opportunistic infections in immunocompromised patients.

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Further reading