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The role of mobile genetics elements in the emergence of superbugs.

INTRODUCTION

"Horizontal genomics" is a new area of prokaryotic biology that investigates DNA sequences present in the chromosome that appear to have originated from other prokaryotes or eukaryotes. Plasmids, bacteriophages and transposons encode the capability to mobilise from one host to another [1]. Qin, Galloway-Pena et al stated that the gain of mobile genetic elements carrying antibiotic resistance, virulence and/or fitness factors are the driving force behind the recent success of the superbugs [2]. Investigations of gene clusters that are associated with vancomycin resistance and methicillin resistance reported that horizontal gene transfer occurs between prokaryotes [3,4,5]. In addition, the esp virulence gene is located on a large pathogenicity-associated island in E. faecium and this esp PAI can be transferred horizontally and inserts in a site-specific manner [6,7]. MGEs are transferred to human isolates and thereby add to the burden of the disease caused by E. faecium, for example, by transferring vancomycin resistance between bacteria. This capability is important to consider, since these genes were shown to be transferred to human isolates and to more virulent organisms such as Staphylococcusaureus[2].A study by Call et al. (2010) analysed five E. coli and Salmonella plasmids carrying gene (blaCMY-2) encodes an AmpC-type beta-lactamase that hydrolyzes third-generation cephalosporins and represent share a common ancestor with the Yersinia and Photobacterium plasmids [8]. Although bacteriophages carrying antibiotic resistance genes have been identified in most of pathogenic bacteria [9, 10]. Their function in the distribution of virulence factors and antibiotic resistance genes has been widely recognised [11]. In this study we will focus on the mobile genetics element of the five riskiest superbugs which are Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas and Enterobacterto identify the role of mobile genetics element in evolution of antibiotic resistant bacteria that invading communities worldwide.

MATERIAL AND METHOD

Plasmid identification:

Plasmid genomes were obtained from the sequence of their hosts that were available from the NCBI database and antibiotics resistant encoding genes were predicted from these genomes of the plasmid by the genebank annotation.

Sequence clustering and phylogenetics:

Mauve progressive alignments to determine conserved sequence segments most likely to be conserved in recombination events were determined using the Mauve algorithm. The guide trees of several-selected plasmid were constructed with Mauve and tree was visualized using FigTree.

RESULTS AND DISCUSSION

Mobile genetics elements:

Transposon (Tn):

Many transposons have been described in the riskiest superbugs that carrying genes encoding resistance to antimicrobials (Table1). Genes encoded resistance to Tetracycline, Vancomycin, Erythromycin, gentamicin, and mercuric chloride were found carried by transposon in Enterococcus.Streptogramin, Macrolide-lincosamideSGB (MLSb) were carried by Tn5406, Tn554 and Tn3853, respectively in staphylococcus. InKlebsiellaTn1331 and Tn4401 has stated to carry Amikacin, Ampicillin, Kanamycin, Streptomycin, Tobramycin and [beta]-lactamases. Resistance genes that known almost resistant to all antibiotics were found in TnAbaR! in Acinetobacter.Aminoglycoside and beta lactam antibiotics were encoded by Tn1331 that carried by Enterobacter. Tn1545 andTn916 both play an important role in the resistant to Tetracycline.

Plasmids:

Many plasmids have been described in superbug'sspecies that confer resistance to antimicrobials and heavy metals. According to the National Center for Biotechnology Information NCBI Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas andEnterobacter, which known as the riskiest superbugs, have high number of plasmids (Table 2).

Within the species of Enterococcus, nighty five plasmids were identified and most of these plasmids were found in Enterococcus faecalis (twenty seven plasmids) and Enterococcus faecium (fifty three plasmids), these two species have become an increasing medical concern by their ability to gain and spread antibiotic resistance. Three hundred and nighty plasmids were identified in Staphylococcus species, andmost of these plasmids were carrying by Staphylococcus aureus strains (two hundred and sixty seven plasmids), which is methicillinresistant (MRSA) and it is a worldwide problem in clinical medicine nowadays.

Klebsiellaspecies harbour more than three handers and seventy plasmids and about three hundred forty plasmids were identified in Klebsiella pneumonia which has a death rate around 50%, even with antimicrobial therapy and new antibiotic-resistant strains of K. pneumoniae are emerging [20, 21]. Nearlyone hundred forty from two hundred Acinetobacter plasmids were found in Acinetobacterbaumannii strains. It has documented to be amongst the most difficult multidrug-resistant gram-negative bacilli to treat and control [22]. Pseudomonas and Enterobacterharbournighty five and eighty-eight plasmids mostly in Pseudomonas aeruginosa, which is a prototypical "multidrug resistant (MDR) pathogen", and Enterobactercloacae that known as a member of the

normal gut flora [23](Table 2).

To characterise the plasmid complement of these bacteria in silico the plasmids were annotated to identify whether or not these plasmids encoded antibiotic resistance genes. In addition, a comparative analysis was made with the plasmid sequences that were publicly available. Analysis of plasmid genome content across all of the publicly available genomes of the six most problematic superbugs that have became increasing medical concerned revealed relationships based on shared DNA sequences (Figure 1).

From the comparative analysis of the plasmids most of the plasmids isolated from specific species were grouped together. Clade A contains different range of plasmids from gram negative species only (Enterobacter, Acinetobacter, Pseudomonas and Klebsiella) which indicated that plasmids grouped in this clade are gram negative specific plasmids and could be transfer from one species to another. However, Staphylococcus plasmid revealed relationships with plasmids from gram positive and gram negative bacteria (Enterococcus and Acinetobacter) which indicate that Staphylococcus, Enterococcus and Acinetobacter share similar types of plasmids (clade C and D). Acinetobacter harbor two different types of plasmid grouped in clade B and D. Acinetobacter plasmids in clade B seem to be specific to this species (Figure 1).

Disease treatment and growth promotion could explain the multiple antimicrobial resistances of most superbugs, including animal strains. The delivery of low levels of antimicrobials has apparently resulted in considerable colonisation of animals with antibiotic resistant bacteria, such as E. coli strains and acquisition of resistance in E. coli in the intestinal flora of the farmers has been described [24, 25]. Aarestrup (2000) reported that resistance to streptothricin antibiotics has been described in Gram-negative bacteria as a result of using nourseothricin as an antimicrobial feed promoter in industrial animal farms in Germany. In addition, resistance to streptogramins may be related to the use of virginamycin, as a feed promoter combined in agriculture for animal food production [26]. In anther hand, mobile genetics elements play an important role of the emergence and the spread of multidrug resistance bacteria. "Horizontal genomics" is a new area of prokaryotic biology that investigates DNA sequences present in the chromosome that appear to have originated from other prokaryotes or eukaryotes. Plasmids, bacteriophages and transposons encode the capability to mobilise from one host to another [27]. Galloway-Pena et al (2012) stated that the gain of mobile genetic elements carrying antibiotic resistance, virulence and/or fitness factors are the driving force behind the recent success of superbugs as an opportunistic pathogen in hospitals. Investigations of gene clusters that are associated with vancomycin resistance and Tn1546 in E. faecium, reported that horizontal gene transfer occurs between human and animal E. faeciumisolates [2, 3, 4, 5]. MGEs are transferred to human isolates and thereby add to the burden of the disease caused by E. faecium, for example, by transferring vancomycin resistance between bacteria. This capability is important to consider, since these genes were shown to be transferred to human isolates and to more virulent organisms such as Staphylococcus aureus[2].

Most research intended at antibiotic resistant bacteria has inspired on attacking the bacteria and developing new antibiotics, nevertheless, instead we have to come at the problem from the host such as observing ways the patient's immune system can be altered to prevent susceptibility to infection, attacking mobile genetics elements and mutations that known to encode antibiotics resistance as well as start a critical thinking of using medical plant and soil microbiom to produce new antibiotics. Targeting antibiotic resistant bacteria with CRISPR and phages can sensitize the microbes to the drugs, targeted killing and plasmid removal. The CRISPR can be designed to target unique sequences in the bacterial chromosome or in harbored plasmids. CRISPR antimicrobials can target specific sequences in a single virulent bacterial species, or even an antibiotic resistance gene. Another approach for CRISPR antimicrobials is to associate them with both replication-competent phages and antibiotics [28, 29]. These techniques open a wide range of applications for the delivery of CRISPR based antimicrobials that are otherwise poorly addressed by traditional antibiotics. Recently, data on the antimicrobial activity of several plants have been scientifically established, beside the cumulative number of studies on pathogenic microorganisms resistant to antimicrobials. Plants products may possibly control microbial growth in varied situations and in the certain case of disease treatment, several studies have considered to define the chemical composition of plant antimicrobials and the mechanisms elaborate in microbial growth inhibition, either separately or connected to predictable antimicrobials [30].

Conclusion:

Using antimicrobials as growth promoters in livestock production and the typical treatment for bacterial infections which is a bactericidal and synergistic mixture of a cell wall synthesis inhibitor such as a [beta]-lactam antibiotic or glycopeptide, with an aminoglycoside has been described as reasons of the emergence of bacteria with high-level resistance The typical treatment for bacterial infections is a bactericidal and synergistic mixture of a cell wall synthesis inhibitor such as a [beta]-lactam antibiotic or glycopeptide, with an aminoglycoside. However, the efficacy of this combination has been compromised by the emergence of bacteria with high-level resistance. The increasing occurrence of multi-resistant pathogenic bacteria is formed a critical demand in the modern world for new rational approaches and strategies to the screening of antibiotics with an extensive spectrum of activity, that can resist the inactivation processes exploited by microbial enzymes.

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[25.] Marshall, B.M. and S.B. Levy, 2011. "Food animals and antimicrobials: impacts on human health." Clin Microbiol Rev., 24(4): 718-733.

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Ashwag Shami

Assistant professor, Biology, Princess Nourahbint Abdulrahman University, Riyadh, Saudi Arabia,

Received 28 February 2017; Accepted 22 March 2017; Available online 17 April 2017

Address For Correspondence:

Ashwag Shami, Assistance phosphorus, Biology, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia, E-mail AYshami@pnu.edu.sa

Caption: Fig. 1: Cladogram tree of the superbug's plasmids Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas and Enterobacter). The tree is based on an alignment of the amino acid sequence of 95 plasmids.
Table 1: The appearance of antibiotic resistance genes carried by
transposon in six of the most important superbugs (Enterococcus,
Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas
andEnterobacter).

Superbugs         Tn        Antibiotic resistance
                            carrying by the Tn

Enterococcus      Tn1545    Tetracycline resistance [12]
                  Tn916     Tetracycline resistance [13]
                  Tn5397    Tetracycline resistance [13]
                  Tn1549    Vancomycin Resistance [14]
                  Tn5335    Erythromycin, gentamicin, and
                              mercuric chloride [15]
Staphylococcus    Tn5406    Streptogramin [16]
                  Tn554     Macrolide-lincosamide-SGB
                              (MLSB) antibiotics[16]
                  Tn3353    Macrolide-lincosamide-SGB
                              (MLSB) antibiotics[16]
Klebsiella        Tn1331    Amikacin, ampicillin, kanamycin,
                              streptomycin, and tobramycin [17]
                  Tn4401    [beta]-lactamases [18]
Acinetobacter     TnAbaRl   45 resistance genes and almost
                              resistant to all antibiotics
Pseudomonas       Tn1545    Tetracycline resistance [19]
                  Tn916     Tetracycline resistance [19]
Enterobacter      Tn1331    Aminoglycoside and beta lactam
                              antibiotics [20]

Table 2: The appearance of antibiotic resistance genes carried by
plasmid in six of the most important superbugs (Enterococcus,
Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas
andEnterobacter).

Superbugs         No of      Antibiotic resistance genes carrying by
                  Plasmids   the plasmids

Enterococcus      95         Tetracycline, Streptothricin,
                             Vancomycin, Erythromycin, Cytolysin,
                             Chloramphenicol, florfenicol,
                             Tigecycline, Daptomycin, Kanamycin,
                             Streptomycin and Teicoplanin.

Staphylococcus    390        Vancomycin, Mupirocin, Neomycin,
                             Tetracycline, Chloramphenicol,
                             Streptomycin, Spectinomycin, Macrolide,
                             Lincosamide, Streptogramin A and B,
                             Fosfomycin, Pleuromutilin, Trimethoprim,
                             Apramycin, Phenicols, Oxazolidinones,
                             Erythromycin, Gentamicin, Apramycin,
                             Methicillin, Bleomycin, Antiseptic,
                             Isoleucine, Pleuromutilins, Kanamycin,
                             Trimethoprim, Minocycline and
                             Penicillins.

Klebsiella        370        Sulfonamide, Trimethoprim, Quinolone,
                             Acriflavin, Glyoxalase, Bleomycin
                             Tetracycline, Gentamicin, Tobramycin,
                             Amikacin, Streptomycin, Colicin,
                             Tunicamycin, Chloramphenicol,Fosfomycin,
                             Florfenicol, Erythromycin, kanamycin,
                             Neomycin, Apramycin, Trimethoprim,
                             Rifampin and Spectinomycin

Acinetobacter     212        Sulfonamide, Trimethoprim,
                             Aminoglycoside,Gentamicin, Bleomycin,
                             Carbapenem, Amikacin, Kanamycin and
                             Neomycin.

Pseudomonas       97         Sulfonamide, Quinolone, Streptomycin,
                             Spectinomycin, Aminoglycoside,
                             Gentamycin, Penicillin, Tetracycline,
                             Trimethoprim, Beta/lactams and
                             Glyoxalase/Bleomycin.

Enterobacter      94         Trimethoprim, Carbapenem, Quinolone,
                             Sulfonamide, Tetracycline, Streptomycin,
                             Beta lactamase, Aminoglycosids,
                             Gentamicin, Tobramycinm,
                             Chloramphenicol,Metallo/beta/Lactamase,
                             Acriflavin, and Glyoxalase/Bleomycin.
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Date:Apr 1, 2017
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