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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 1  |  Issue : 2  |  Page : 68-78

Integrons as emerging contaminants facilitating the widespread of antimicrobial resistance in Enterobacteriaceae


1 Department of Environmental Health Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates; SAMRC Microbial Water Quality Monitoring Centre, University of Fort Hare, Alice, South Africa; Applied and Environmental Microbiology Research Group, Department of Biochemistry and Microbiology, University of Fort Hare, Alice, South Africa
2 SAMRC Microbial Water Quality Monitoring Centre, University of Fort Hare, Alice, South Africa; Applied and Environmental Microbiology Research Group, Department of Biochemistry and Microbiology, University of Fort Hare, Alice, South Africa

Date of Submission17-Feb-2022
Date of Decision07-Apr-2022
Date of Acceptance08-Apr-2022
Date of Web Publication28-Apr-2022

Correspondence Address:
Folake Temitope Fadare
Department of Microbiology and Biochemistry, University of Fort Hare, Alice 5700
South Africa
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/abhs.abhs_13_22

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  Abstract 

Antibiotic resistance genes (ARGs) are classified as emerging environmental pollutants of global public health concern. These ARGs are disseminated through genetic elements such as integrons. Integrons can acquire, integrate, and express various rearrangeable gene cassettes (GCs), harboring different ARGs that may be readily spread to other bacteria in widely varied niches. Different classes of integrons possessing diverse arrays of ARGs located within its GCs are commonly distributed in the Enterobacteriaceae family and are responsible for the high rate of multidrug resistance observed. The members of this family are natural commensals of the gastrointestinal tracts of humans and animals released into the different aquatic environments. Various water sources further disseminate the organisms and their diverse resistance gene repertoires. Thus, understanding the distribution and diversity of the significant integron classes in the clinically relevant Enterobacteriaceae members will be of utmost importance. It will provide a framework for health authorities to make decisions on surveillance of these contaminants in the environment.

Keywords: Antibiotic resistance genes, Enterobacteriaceae, gene cassettes, integrases, integrons


How to cite this article:
Okoh AI, Fadare FT. Integrons as emerging contaminants facilitating the widespread of antimicrobial resistance in Enterobacteriaceae. Adv Biomed Health Sci 2022;1:68-78

How to cite this URL:
Okoh AI, Fadare FT. Integrons as emerging contaminants facilitating the widespread of antimicrobial resistance in Enterobacteriaceae. Adv Biomed Health Sci [serial online] 2022 [cited 2022 Aug 11];1:68-78. Available from: http://www.abhsjournal.net/text.asp?2022/1/2/68/344316




  Background Top


Members of the family Enterobacteriaceae are commonly associated with several community-acquired and hospital-acquired infections. The family’s genera can be found in the gastrointestinal tracts of warm-blooded animals, humans inclusive, and plants, soil, and water. Clinically significant genera include Escherichia-, Citrobacter-, Klebsiella-, Enterobacter-, Salmonella-, Shigella-, Serratia-, and Yersinia. Intestinal, genitourinary, and bloodstream infections have been linked to these microbes [1]. Antibiotics are used extensively in clinical and farming contexts to treat these infections. The fast rise of multidrug-resistant (MDR) microorganisms, particularly among these intestinal microbes, has been exacerbated by the use and overuse of antibiotics during the previous few decades. This necessitates an upsurge in the clinical failures observed with the currently available antibiotics, which is expected to rise if left unchecked.

The capacity of a bacteria to acquire and subsequently transfer antibiotic resistance genes (ARGs) to others in wide-ranging niches via horizontal gene transfer (HGT) mechanisms has been essential in the development of MDR phenotypes. The three mechanisms of HGT include transformation, which entails the direct uptake of DNA from its surroundings; conjugation involves cell-to-cell contact, whereas transduction consists of a vector for the insertion of DNA into the recipient cell. Once the newly incorporated DNA is in the cell, site-specific recombination or transposition can further spread the ARGs to plasmids, chromosomes, transposons, and integrons present in the recipient bacteria. These genetic elements then act as the primary vehicles facilitating the HGT. Integrons play a significant part in spreading antibiotic resistance, especially in Gram-negative pathogens [2,3].

Integrons are genetic elements that act as natural gene capture and expression systems. Although integrons by themselves are immobile, they can link with other DNA elements. Transposons, conjugative plasmids, and insertion sequences (IS) elements are examples of DNA elements that can act as an essential vehicle for ARG transmission [4]. Generally, integrons are distinguished by their capacity to acquire small mobile elements known as gene cassettes (GCs) [5]. However, about one-third of them have been found in bacterial genomes without GCs and were called empty integrons. They are present in approximately 17% of bacterial chromosomes [6]. These structures have been detected in various environments, including Antarctic soils, desert soils, forests, hot springs, plant surfaces, and sediments of river, marine, and deep-sea. In the late 1980s, integrons were identified and subsequently implicated in the distribution of ARGs through the presence of GCs, which they usually harbor. Integrons are now well-established and well-documented in disseminating resistance, especially within Gram-negative bacteria [2]. Hence, in this review, we carried out an overview of the distribution and diversity of the different integron classes in the clinically relevant Enterobacteriaceae members.


  Integron structure Top


Structurally, three essential properties of all integrons are found on a functional platform known as the 5′ conserved segment (CS). These are the gene integron integrase, intI, which encodes a site-specific tyrosine recombinase enzyme, with a primary function of catalyzing the integration and excision of GCs. Secondly, an integron-associated recombination site, attI, is recognized by the intI and functions as the site for acquiring new genetic material without disturbing the previously existing genes. Lastly, an effective constitutive promoter, Pc, regulates the expression of captured GCs. It is located within the intI gene and oriented towards the integration point [7]. These basic features ensure that in a population of integron-containing cells, the newly created variants can instantly express genes that are likely to confer phenotypic advantages due to the presence of the promoter. The level of expression of the GCs is contingent on its proximity to the promoter, Pc, where the maximum level of expression occurs in the GC closest to the promoter [6]. Therefore, integrons are essentially genetic elements capable of integrating and expressing various rearrangeable GCs harboring different ARGs that may be readily mobilized to any other neighboring bacteria.


  Gene cassettes Top


These are variable sequences that can exist as free, circular, nonreplicating DNA molecules and are usually linear when integrated into more prominent elements called integrons. GCs do not carry the machinery for their movement and are referred to as the mobile parts of an integron [8]. Their presence has been known to confer resistance against most classes of antibiotics. These include all known β-lactams, chloramphenicol, trimethoprim, erythromycin, aminoglycosides, quinolones, streptothricin, lincomycin, rifampicin, fosfomycin, and antiseptics of the quaternary ammonium compound family [9]. The GCs have simple structures with two components which are an open reading frame (ORF) which encodes ARGs, and a cassette-associated recombination site (attC), also called the 59-basepair element (59-be) and therefore used interchangeably in this text. These 59-be, which usually vary in length (generally between 57 and 141 bases), are imperfect inverted repeat sequences (IRs) that are found at the ORF’s 3′ end and are recognized by the integrase (intI) [2].

The 59-be is an essential component for integrating GCs into integrons. The recombination of the 59-be in a closed-circular cassette molecule with the attI results in integrating GCs into the integron. Moreover, the excision of a GC occurs between two 59-be resulting in the formation of a free circular cassette [10]. There is a strong association between the attI and 59-be sites ensuring that new GCs are inserted next to the integron irrespective of the integron already harboring one or more GCs. The result of this system implies that the last GC integrated is the most proximal to the promoter [11], as seen in [Figure 1]. As this association is conservative, the attI site is reconstituted; it can occur numerous times, thus making it possible for a particular integron to harbor a string of GCs. Individual intI is strictly associated with its attI site, but this does not apply to the attC. Therefore, even though there is a great diversity in the sequences of the attC sites, each different intI can recognize many other attC sites, thereby allowing GCs to be easily exchanged between different integron classes [5]. The majority of the GCs do not possess a promoter and therefore depend on an external promoter, Pc, located on the intI of an integron located upstream for their expression [2]. Therefore, a promoter-less cassette must be closely situated to the Pc on an integron to express genes on its cassette. It thus implies that the downstream genes on integrons with a long array of cassettes may be unexpressed. The insertion event positions the gene in the cassette in the proper orientation, allowing expression from the integron’s upstream promoter, Pc [5]. The GC is flanked at both ends by the conserved sequences’ GTTRRRY’.
Figure 1: Organization of an integron and gene cassette (GC) recombination system. The integron integrase, intI gene, catalyzes the insertion of the GC3 at (A) and the excision of GC1 at (B). The integron recombination site, attI, is strongly associated with the GC’s recombination site, attC (also known as 59-be). As shown in (A), the circularized GC3 is inserted into the integron and becomes linearized through a particular recombination process between the attI site and the attC3 of the incoming GC3. Hence, the GC3 is placed closest to the promoter, Pc. The excision of the GC occurs preferentially between two attC sites. The GC1 is removed by recombination between attC1 and attC3 sites at (B). The arrows indicate the direction of transcription.

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  Classes of integrons Top


Integrons have been categorized into various classes based on the amino acid sequence of the intI gene [8]. Integrons with intI1 genes are classified as class 1, those with intI2 genes are class 2, those with intI3 genes are class 3, and so on. The intI1, intI2, and intI3 were identified with mobile genetic elements, whereas intI4 and others were associated with chromosomal integrons [4]. Most of the integrons that have been reported have been detected in Gram-negative bacteria, with very few detected among Gram-positive bacteria [1]. Class 1 and 2 integrons have been mostly reported among the Enterobacteriaceae family, whereas class 3 integrons seem to be far scarce and, consequently, infrequently implicated in the spread of antibiotic resistance. Members within the same class have the same integrase but can be further differentiated based on their GCs. Integrons have been identified in several bacterial species from clinical and environmental samples [2].

The other integrons classes, including classes 4 and 5, have not been extensively studied. They are yet to be reported within the Enterobacteriaceae family. In Vibrio spp., a class 4 integron was discovered. It was inserted in an integrative and conjugative element (ICE) and conferred resistance against trimethoprim/sulfamethoxazole [12]. A class 5 integron was also found in a compound transposon on the Vibrio salmonicida pRSV1 plasmid [13]. The attI sites of each integron class differ, although they all have a common core site with the conserved sequences. Therefore, there is little comparison between the sequences of attI1 present in class 1 integrons and the corresponding sequences of attI2 and attI3 present in class 2 and 3, respectively [5].


  CLASS 1 INTEGRONS Top


In 1989, the first integron discovered was the Class 1 integron by Stokes and Hall [14]. The class now accounts for a substantial proportion of MDR nosocomial infections. It is the most frequently reported integron among the enterics and has been reported in pathogens such as Salmonella, Escherichia coli, Enterobacter, Citrobacter, Shigella, Yersinia, Klebsiella, Serratia, and Proteus [3]. Class 1 integrons have the highest detection frequency among the other integrons. The intI1 can recombine with different attC sites even when their nucleotide sequences are very dissimilar. The attC sites are usually associated with a particular ORF in the GCs, which are not necessarily integrated. Once integrated, they become part of the integron enabling this class to harbor the most known antibiotic resistance GCs. The class 1 integron-integrase (intI1) can recruit GCs from other classes [4].

A typical class 1 integron is associated with functional and nonfunctional transposons derived from Tn402. These structures are usually embedded in a large transposon such as Tn21/Tn1696 with a 5′ region called the 5′-CS [8]. The 5′-CS consists of an integron’s three essential features, intI, attI, and Pc. In addition, many of the class 1 integrons have a 3′ region, also called 3′-CS. The length of the sequences of the 3′-CS is typically 2,384 bp and encodes four ORFs [14]. The first is the qacEΔ1 gene, a truncated version of the qacE conferring resistance against quaternary ammonium compounds. A postulation was that the truncation arose due to the insertion of a sul1 gene at the 3′ end. The gene encodes resistance against sulphonamides. The insertion led to the deletion of the 59-be of the qacE gene and some coding sequences. The sul1 is the second ORF on the 3′ end to further lend credence to this theory. It encodes resistance against the antibiotic sulphonamide through the enzyme dihydropteroate synthetase [2]. The third is the orf5, a gene of unknown function, although it is similar to puromycin acetyltransferase. The last is the orf6, whose biological function is not yet ascertained [1]. The schematic representation of a typical class 1 integron is shown in [Figure 2].
Figure 2: A schematic illustration of a typical class 1 integron structure. The 5′-CS harbors the integrase gene (intI1), the promoter (Pc) and the attachment site (attI), whereas the 3′-CS contains four ORFs (qacEΔ1, sul1, orf5, and orf6, respectively). The hatched box shows a single gene cassette with its corresponding 59-be inserted between the 5′ and 3′ CS. The common promoter usually expresses the gene found proximal to the 5′ site of insertion.

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It has been reported that the presence of the qacE gene protects the bacterial cells from toxins found in their natural environment. The gene encodes multidrug exporters that confer resistance against bactericidal ammonium molecules. The qacE gene has been reported in over half of the GCs detected in class 1 integrons recovered from environmental isolates [15]. In the early 1930s, which was the era preceding the discovery of antibiotics, quaternary ammonium compounds served as disinfectants in hospitals [16]. This explains the possession of the qacE gene in most class 1 integrons. The first broadly introduced antibiotics in the mid to late 1930s were the sulphonamides, commencing antibiotic resistance selection. Therefore, it was not unexpected that the detection of the sul1 gene on the class 1 integrons was the next event of evolution. The general abundance of class 1 integrons in other ecosystems apart from the clinical settings where they seemed to have originated makes them be referred to as the pollutants of the natural environment [2].

Some enteric bacteria have been reported to have variations in the 3′-CS, which is inconsistent with most known class 1 integrons. An example is observed in the Class 1 integron in Tn402, with a complete qacE GC without the sul1, orf5, and orf6 genes. Immediately after the qacE gene, it contains the genes tniR, tniQ, tniB, and tniA, which are referred to as the transposition gene module (tni module) on the 3′ end [17]. Tn402 has typical inverted repeats of 25bp, flanking the integron, IRi, and the transposition modules, IRt [Figure 3]. These IRi and IRt bordering the integron enable class 1 integrons within the Tn402 to move horizontally through transposition. Many class 1 integrons do not have this complete tni module, as several additions and deletions have rendered it a defective transposon [17,18]. For example, integron In2 has an insertion of IS1326 and IS1353 located at the 3′-CS giving rise to the deletion of parts of the tni module [18]. Hence when the evolutionary history of class 1 integrons is considered, the Tn402 is regarded as the ancestral lineage of class 1 integrons. Various evidence show complex integrons in different bacterial species with numerous discrepancies in the functional structure and ORFs harboring different GCs [2].
Figure 3: Representation of a class 1 integron found in Tn402 named In16. Three gene cassettes, dfrB3, orfD, and qacE with their individual 59 -be represented by filled rectangles are harbored on this integron. The complete transposition gene modules are located downstream of the cassettes. The structure is bounded by 25bp inverted repeats, IRi and IRt, as indicated by the thick line. The arrows show the direction of transcription.

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  CLASS 2 INTEGRONS Top


Class 2 integrons are also found within transposons called Tn7 and their related transposon derivatives, such as Tn825, Tn1826, and Tn4132, which facilitate their dissemination [19]. Their 3′-CS harbors five tns genes (tnsA, tnsB, tnsC, tnsD, and tnsE) which are also involved in their movement. They contain integrase genes (intI2) whose sequences share a 46% similarity with class 1 integrase (intI1) [2,5]. Within the Enterobacteriaceae family, intI2 occurs less frequently when compared with class 1 integrons [2]. However, the essential distinctive feature is that the intI2 gene is interrupted by an early stop codon with a shortened, nonfunctional 178 amino acid protein product [20]. The intI2 gene’s mutation is liable for the low variety of GCs compared to class 1 integrons [2], giving rise to a stable GC array harboring dfrA1, sat2, aadA1, and orfX genes. The dfrA1 encodes resistance against trimethoprim, whereas sat2 confers resistance against streptothricin. The aadA1 genes confer resistance against streptomycin and spectinomycin, whereas orfX encodes a protein of unknown biological activity [20], as seen in [Figure 4]. The GC orfX is not followed by the usual 59-be with a typical palindromic and core structure, but its activity as a recombination site has been established [20].
Figure 4: The schematic illustration of a class 2 integron from Tn7. The intI2 gene defines the class 2 integron characteristically and is shown in the unshaded rectangle box. An “X” indicates the premature stop codon resulting in the transcription and translation of an inactive integrase. The attI2 site is the class 2 recombination site. The Tn7 harbors three gene cassettes, dfrA1, sat2, and aadA1, with their respective 59-be indicated with the filled rectangles. The last GC is the orfX with an unknown biological activity which contains an unusual 59-be structure. Arrows indicate the direction of transcription.

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There are slight differences reported in the GCs of some class 2 integrons. It has been inferred that these might be due to GCs movements even when the cognate integrase is inactive. It is proposed that these differences might have either been due to the recombination activity supplied by another active integrase from class 1 or the occasional mutation of the stop codon leading to the restoration of recombination activity [21]. Therefore, a typical wild-type class 2 integrase cannot move GCs as its site-specific recombination activity is defective. Two class 2 integrons have been described with functional intI2. One had 9 GCs whose biological activities were unknown. The other harbored the dfrA14 GC and a novel GC which was predicated as a lipoprotein signal peptidase gene [22]. There had been only five class 2 integrons characterized, and each was associated with antibiotic resistance before the reports of active intI2 integrases.

Further inference from the report of Márquez et al. [22] suggests that active class 2 integrase, as described above, exists but is not widespread. For instance, a hybrid of class 2 integron in Acinetobacter baumannii was reported by Ploy et al. [23]. The integron contained an intI2 gene, with two GCs usually found on class 2 integrons, dfrA1 and sat, in addition to the 3′-CS of class 1 integrons. This description of a hybrid integron shows that recombination between two different integron classes is indeed possible.


  CLASS 3 INTEGRONS Top


Class 3 integron integrase genes (intI3) share 60% of their sequence identity with class 1 integrons. They are also embedded in Tn402 but have a reverse orientation compared with class 1 integrons [24]. Although rapidly evolving, they are the least prevalent integrons class, colonizing new species and acquiring novel GCs. Their GCs mainly confer resistance against aminoglycosides and β-lactams [2]. The class 3 integron was initially reported in a Serratia marcescens strain Tn9106 recovered from a patient in Japan who was diagnosed with a urinary tract infection. The integron harbored two GCs. One was the blaIMP which encodes resistance against carbapenems, broad-spectrum Metallo-β-lactamases. The second was the aacA4 which encodes resistance against aminoglycosides. This was the first report of the blaIMP gene on an integron, although the aacA4 gene had been earlier identified in class 1 integrons [25]. The class 3 integron is flanked by IRi and a resolvase-encoding tniR gene at the 3′ -CS end [24]. Such class 3 integrons are quite common in Japan [26] and were not usually detected in other parts of the world [27]. However, they have been reported in Canada [28] and, more recently, Iran [29] and Portugal [30]. They also do not harbor a wide array of GCs, which is probably due to the capacity of the intI3 gene being less active than the intI1 and intI2 integrases [11]. Class 3 integrons, although not as widely disseminated as class 1 integrons, have the potential of playing an essential function in the widespread of ARGs. Unlike the typical class 2 integrase, the class 3 integrase is active. It catalyzes the site-specific recombination between GCs, just as in class 1 integrons [24].


  Integrons and their role as an emerging contaminant Top


Antibiotic pressure may have had a critical impact on the selection and spread of integrons in bacteria. Over 130 GCs impart resistance against diverse antibiotic classes, whereas over 60 GCs with unknown functions have been identified [4]. GCs have conferred antibiotic resistance in practically every antibiotic family. Furthermore, the GCs harboring the qacE, which encodes resistance against the quaternary ammonium compounds, are also found in integrons [21]. Integrons were detected in bacterial populations under direct or indirect antibiotic pressure in clinical, agricultural, and environmental contexts, according to studies [2,3]. Many bacteria containing integrons and resistance genes from wastewater make their way into the environment due to the high rate of integrons in commensals in humans and animals.


  Integrons in different water matrices Top


It has been estimated that only 1% of the wide range of bacteria found within the environment is culturable using the various available cultivation techniques. To overcome this limitation, more researchers have developed methods based on metagenomes. The metagenomic approach, together with cultivation techniques used to study bacterial communities found in the environment, has highlighted the roles of integrons in disseminating antibiotic resistance. So, there is mounting evidence that the environment plays a critical part in disseminating antibiotic-resistant bacteria impacting human and animal health [31].

Integrons were found in estuarine, stream water sediments and biofilms, creek, and lake sediments using metagenomic and culture-dependent approaches. In some of these reports, the integrons harbored one to three GCs with many unknown functions. Water has gotten a great deal of attention since it is the primary vector of contaminants in the environment. ARGs have been reported in freshwater bodies, including rivers [31], hospital effluents [32], and sewage effluents [33]. [Table 1] shows the distribution of various GCs in the integron classes among some members of the Enterobacteriaceae family in different environmental matrices. The majority of the GCs encode the dfrA gene, which confers resistance against trimethoprim. Others include the aadA and aac(6)-Ib, which confers resistance against the aminoglycosides. The sat2 and sat1 encode resistance against streptothricin, whereas the blaIMP and blaOXA encode resistance against β-lactamases. The majority of the GCs were detected in class 1 integrons, whereas class 3 integrons were the least. Class 3 integrons were detected in hospital effluents and mostly harbored the β-lactamases.
Table 1: Distribution of gene cassettes in the integron classes among some members of the Enterobacteriaceae family in different environmental matrices.

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  Integrons in wastewater treatment plants Top


The wastewater treatment plants (WWTPs) link human waste and the aquatic and soil ecosystems. WWTPs gather effluents from several sources, including private residences, hospitals, factories, and animal husbandries. As a result, the influents of the WWTP include microbiological, chemical, and organic wastes. Due to the high bacterial density in these WWTPs, they are hotspots for HGT, with numerous recombination events coexisting since wastewater releases traces of antimicrobial agents and resistance determinants [33]. At various stages of the WWTP process, Class 1 integrons have been identified, with varying prevalence or relative abundance [42]. Unfortunately, the presence of these genetic elements in WWTP’s final effluents shows the inadequacy of the procedure for removing bacteria that harbor them. These may, in turn, contribute to the increased frequency of integron-positive isolates and their elevated resistance level.


  Integrons in some clinically relevant enterobacteriaceae Top


The relationship between integrons and antibiotic resistance has been mostly considered within the family of Enterobacteriaceae. The members of this family are usually of clinical and veterinary interest. The continuous use of antibiotics within the medical and agricultural settings has accelerated the dissemination of integrons as they harbor various ARGs. The class 1 integrons are the most often detected. They have been reportedly found in multiple niches, including their detection in commensal bacteria of farm animals, healthy humans and even infants not yet exposed to antibiotics [43,44]. These commensal bacteria harbor integrons with varying structures and play a critical role in transferring resistance genetic markers from commensal bacteria to environmental and pathogenic bacteria.

Escherichia coli

The bacterium E. coli is a dominant free-living organism that has been extensively studied. It is the most ubiquitous facultative anaerobe in the gut microbiome of humans. It is commonly found in animals’ gastrointestinal tract, thereby fostering its presence as an indicator of fecal contamination. It has been reported as an important human pathogen causing various intestinal and extraintestinal illnesses [9]. Antibiotics are commonly used to treat infections arising from this organism, resulting in selected antibiotic-resistant strains. A substantial relationship between an enhanced rate of resistance and integrons in various environmental matrices from different geographical locations has been reported. It indicates the functions of integrons in disseminating ARGs, and the emergence of E. coli with multidrug resistance traits has been well established in the past few decades [43,44].

Escherichia coli harboring class 1 integrons were initially reported from European countries before their detection in other parts. The integron 1-positive isolates harbored various GCs in diverse combinations. The most frequently observed occurred either singly or in combination. They conferred resistance against trimethoprim (dfrA1, dfrA5, dfrA12, dfrA17, and dfrB2), erythromycin (ere2), and streptomycin, aminoglycosides, and spectinomycin (aadA1, aadA2, and aadA5) [34]. The most predominant GC among the integron-mediated antibiotic resistance in E. coli in the 1980s was aadA1. It was followed by the combination of GCs dfrA17-aadA5, which evolved in the 1990s. The presence of the aadA gene in integron class 1 and 2 indicates that a selection mechanism for the propagation of this GC in enteric bacteria exists [36]. Su et al. [45] in China from 1998 to 2004 reported a higher occurrence of multigene cassettes in the clinical E. coli isolates recovered in the final year than when the study commenced. Over time, the increase in the prevalence of combination GCs indicates that class 1 integrons are implicated in acquiring resistance against broad-spectrum antibiotics. An example of integron-positive E. coli harboring a variety of GCs is a pathogenic E. coli strain isolated from a hospitalized patient in France. The isolate harbored a class 1 integron named In53 which contained nine functional GCs coding for resistance against various compounds. These GCs include aacA1b/orfG (amikacin, tobramycin, and netilmicin), aadA1 (spectinomycin and streptomycin), aadB (gentamicin), arr-2 (rifampicin), blaOXA-10 (penicillin), blaVEB-1 (extended-spectrum β-lactamase, (ESBL)), cmlA5 (chloramphenicol), qacI [46]. The common GCs harbored in this class 1 integron result in the resistance against aminoglycosides, trimethoprim, erythromycin, and the β-lactams.

Although many class 2 integrons have also been detected in numerous commensal, environmental, and pathogenic E. coli, their occurrence has been much lower than their class 1 integron counterpart. The lower rate is attributable to the presence of the defective class 2 integrase. There is a predominance of the GC combination dfrA1-sat1-aadA1 in E. coli globally [44,45]. In comparison, another GC array with a slight modification in the sat allele has also been reported (dfrA1-sat2-aadA1) [35]. A novel class 2 integron with a functional intI2 gene in a pathogenic E. coli has been reported. The integron possessed a GC dfrA14 typically found in class 1 integrons and a novel ORF. The existence of a functioning intI2 gene suggests that these integrons are no longer reliant on other mobilizing elements and have developed the ability to capture and distribute these genes to other bacteria [22]. Class 3 integrons have not been often discovered in prior investigations, and when they are, they co-occur with class 1 and class 2 integrons in MDR isolates, indicating that class 3 integrons may play a vital role in the spread of antibiotic resistance in the near future.

Klebsiella spp.

Klebsiella species are omnipresent in nature. They are mostly found in two major habitats. First is environmental sources, including soil, surface water, plants, and sewage. The other is in the mucosal surfaces of warm-blooded vertebrates such as horses, swine, or humans [47]. They also constitute members of the microbiome of the human gut. There are three major clinically important species of this genus. The most important is Klebsiella pneumoniae (responsible for 75% to 86% of Klebsiella infections), followed by K. oxytoca (accountable for 13% to 25% of Klebsiella infections) and less commonly K. granulomatis [47]. The two most common pathogens have been implicated in human infections. Examples are meningitis, urinary tract infections (UTI), wound infections, cholecystitis, pneumonia, and septicaemia. These species have acquired resistance to many antibiotics, including extended-spectrum β-lactams, cephalosporins, and aminoglycosides. The first carbapenem-hydrolyzing enzyme was isolated from a K. pneumoniae strain in North Carolina in 1996 and named Klebsiella pneumoniae carbapenemase (KPC) [48]. Shortly after, this enzyme spread rapidly among other members of the Enterobacteriaceae and, within two decades, became a global public concern. Due to an aggravated incidence of MDR K. pneumoniae and the associated resistance challenges they pose, they have been included in the ESKAPE pathogens list. The inclusion of resistance genes within mobile elements, particularly integrons, has been ascribed to the MDR trait’s great potential to propagate rapidly in Klebsiella spp. The class 1 integrons in this genus have been extensively investigated and reported to harbor a variety of GCs. The most associated GCs are aadA and dfrA, although multiple resistance traits have reported the dfrA-orfC and dfrA12-orfF-aadA2 [49]. Some novel GCs reported include aacA4-catB8-aadA1 and aadB-catB-like-blaOXA-10/aadA1. Some class 2 integrons have typical GCs dfrA, sat1/sat2, and aadA1 [50], whereas class 3 harboring blaGES-1 has also been previously reported [26].

K. pneumoniae are generally known to produce the enzymes blaTEM, blaSHV, and blaCTX-M ESBLs. The genes that produce these enzymes may be found as independent entities or in complex integrons enhancing their rapid spread to other pathogens with evidence of several reports of higher integrons in ESBL producers than in their non-ESBL producers [51]. Thereby further revealing the pivotal role integrons play in transferring extended-spectrum resistance.

Salmonella spp.

Salmonella is the causative agent of salmonellosis, a global zoonosis and a foodborne disease posing a significant public health risk. They have been frequently reported in water and are commonly isolated foodborne pathogens of dairy products, poultry and eggs, fruits, and vegetables. With a repertoire of over 2600 serovars, those implicated in enteric fever include Typhi, Sendai, and Paratyphi A, B, and C. The nontyphoidal Salmonella includes serovars such as Enteritidis and Typhimurium [52]. Since the development of MDR Salmonella in 1990, they have posed a significant public health concern and are associated with different integrons classes with the usual presence of one to three antibiotic resistance GCs. Various reports establish that their MDR traits have been harbored by different classes, with the most prevalent being class 1 integrons. The majority of these integrons are present on conjugative plasmids and may be readily transferred to other strains, giving rise to similar GCs found in environmental, food, and human strains. The class 1 integrons have been more often involved in the widespread ARG in Salmonella spp. Class 1 has several variants of GCs encoding resistance against trimethoprim (dfrA1, dfrA7, dfrA12, dfrA17), aminoglycosides (aadA, aadA1, aadA2, and aadA5), gentamicin and kanamycin (aadB) either alone or in combination. Ab initio, only single GCs were reported among the different Salmonella serovars. However, just as seen in other members of Enterobacteriaceae, the occurrence of integrons harboring multiple GCs has increased over time. Several reports of novel and atypical class 1 integron-mediated GCs in Salmonella spp. emerged. For example, the unusual GC array aac(6′)-IIc, ereA2 and aadA2 in Salmonella enterica serovar Keurmassar was reported in Senegal [53], whereas the array dfrA21-blaOXA-129-aadA1 was reported in S. enterica serovar Bredeney in Brazil [54]. The significant variety of class 1 integrons in terms of GCs, location, and distribution in different serovars shows a vital role in disseminating resistance genes among Salmonella spp.

Class 2 integrons have also been detected in this bacterium, albeit at a relatively lower occurrence percentage than class 1. No class 3 integrons in Salmonella using molecular confirmation methods have been reported. The serovars of Salmonella harboring class 2 integrons have a seemingly consistent GC array of dfrA1-sat1-aadA1 [55]. However, an array replacing sat1 with sat2 was observed in S. enterica serovar Paratyphi B dT+ strains. Novel GC with arrays of sat1- ere(A)-aadA1 and sat-sat1-aadA1 were also identified in class 2 integrons among nontyphoid S. enterica serovars in Japan [56].

Shigella spp.

In terms of prevalence and distribution, Shigella spp. is found worldwide. It is the causative agent of shigellosis and continues to be an important cause of diarrheal diseases. Shigellosis is a human colon infection that causes various symptoms, from short-term watery diarrhea to severe inflammatory bowel illness with tenesmus, fever, and neurologic symptoms. It is linked to a high rate of disease, especially in children under the age of five, who account for the majority of cases (70%) and deaths (60%) [57]. The prompt treatment of shigellosis using effective antibiotics has been reported to reduce the period of clinical symptoms and decrease their transmission from person to person.

However, excessive use of these antibiotics has led to a progressive increase in antibiotic resistance. With resistance against ampicillin, trimethoprim/sulphonamides, tetracycline, and streptomycin. The rapid dissemination of the genes mediating this antimicrobial resistance phenomenon has been found on GCs harbored by integrons, especially class 1 and class 2 [49]. Within the Enterobacteriaceae family, there seems to be a high occurrence of class 2 integron being reported in Shigella spp. than class 1 [49].

Enterobacter spp.

This genus was first described in 1960 by Hormaeche and Edwards and has undergone several taxonomic modifications within the last six decades. The members of this genus are facultative anaerobic bacilli which are widely found in nature. As commensals, they are part of the gut human microbiome, whereas as saprophytes, they thrive in soil and sewage [58]. Enterobacter spp. has become clinically significant by emerging as nosocomial pathogens from intensive care patients accounting for 5%–7% of all nosocomial infections in the United States in the past few decades. They are also essential pathogens in plants and insects since they are easily found in terrestrial and aquatic environments [59]. Several Enterobacter spp. have been reported to harbor class 1 integrons with GCs, including aadA2 and dfrA12-orfF-aadA2 [34]. Ramrez et al. [60] found that class 2 integrons containing a typical intI2 GC with additional genes (dfrA1–sat2–aadA1–orfXybfA–ybfB–ybgA) were a prominent GC array in Enterobacter. Class 3 integrons with GCs blaOXA-256 and aac(6′)-Ib have also been found in E. cloacae, conferring resistance against oxacillin and gentamicin, respectively [40].

Citrobacter spp.

The members of this genus are widely distributed and are a significant part of the normal intestinal flora of animals and humans. Species of this genus are also among the several members of the Enterobacteriaceae family, which are the leading cause of neonatal sepsis and meningitis. A large GC array containing a typical intI2 GC with additional genes (dfrA1–sat2–aadA1–orfXybfA–ybfB–ybgA) like the Enterobacter array was reported to be a major GC array in Citrobacter [60]. Recently, a class 3 integron has been identified in Citrobacter spp. with resistance against oxacillin [41].


  Conclusion Top


The Enterobacteriaceae family comprises bacteria that live in the gastrointestinal tract of both animals and humans. Because several species of this family coexist in the gut, where they are constantly exposed to different classes of antibiotics, there is a higher probability that these bacteria will act as possible carriers of resistance gene determinants which should not be underestimated. These resistance genes are often found on GCs which can be easily integrated into integrons and then subsequently expressed, thereby conferring the resistant phenotype on the organism. Integrons also harbor resistance determinants for other antimicrobials and pollutants. The physical relationship between integrons and such resistance determinants may result in their invariable selection, which adds to the complexity and substantially influences public health.

Study limitations

The review is based on the analysis of the available literature. The data may lack some evidence from the clinical perspective.

Authors’ contributions

FFT prepared the review draft and the figure concepts, and OAI provided feedback and intellectual input to the review. Both authors reviewed and approved the final draft of the manuscript. The authors are responsible for the contents and integrity of this manuscript.

Financial support and sponsorship

This work was supported by South Africa Medical Research Council (SAMRC).

Conflict of interest

There are no conflicts of interest.

Data availability statement

Not applicable.



 
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  In this article
Abstract
Background
Integron structure
Gene cassettes
Classes of integrons
CLASS 1 INTEGRONS
CLASS 2 INTEGRONS
CLASS 3 INTEGRONS
Integrons and th...
Integrons in dif...
Integrons in was...
Integrons in som...
Conclusion
References
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