Antibiotic resistance in gram-negative bacteria: the role of gene cassettes and integrons. - Related Documents




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446601.0000Antibiotic resistance in gram-negative bacteria: the role of gene cassettes and integrons. Resistance of gram-negative organisms to antibiotics such as beta-lactams, aminoglycosides, trimethoprim and chloramphenicol is caused by many different acquired genes, and a substantial proportion of these are part of small mobile elements known as gene cassettes. A gene cassette consists of the gene and a downstream sequence, known as a 59-base element (59-be), that acts as a specific recombination site. Gene cassettes can move into or out of a specific receptor site (attl site) in a companion element called an integron, and integration or excision of the cassettes is catalysed by a site-specific recombinase (Intl) that is encoded by the integron. At present count there are 40 different cassette-associated resistance genes and three distinct classes of integron, each encoding a distinct Intl integrase. The same cassettes are found in all three classes of integron, indicating that cassettes can move freely between different integrons. Integrons belonging to class I often contain a further antibiotic resistance gene, sull, conferring resistance to sulphonamides. The sull gene is found in a conserved region (3'-CS) that is not present in all members of this class. Class I integrons of the sull type are most prevalent in clinical isolates and have been found in many different organisms. Even though most of them are defective transposon derivatives, having lost at least one of the transposition genes, they are none the less translocatable and consequently found in many different locations. The transposon Tn7 is the best known representative of class 2 integrons, and Tn7 and relatives are also found in many different species.199816904397
446510.9999Genetic analyses of sulfonamide resistance and its dissemination in gram-negative bacteria illustrate new aspects of R plasmid evolution. In contrast to what has been observed for many other antibiotic resistance mechanisms, there are only two known genes encoding plasmid-borne sulfonamide resistance. Both genes, sulI and sulII, encode a drug-resistant dihydropteroate synthase enzyme. In members of the family Enterobacteriaceae isolated from several worldwide sources, plasmid-mediated resistance to sulfonamides could be identified by colony hybridization as being encoded by sulI, sulII, or both. The sulI gene was in all cases found to be located in the newly defined, mobile genetic element, recently named an integron, which has been shown to contain a site-specific recombination system for the integration of various antibiotic resistance genes. The sulII gene was almost exclusively found as part of a variable resistance region on small, nonconjugative plasmids. Colony hybridization to an intragenic probe, restriction enzyme digestion, and nucleotide sequence analysis of small plasmids indicated that the sulII gene and contiguous sequences represent an independently occurring region disseminated in the bacterial population. The sulII resistance region was bordered by direct repeats, which in some plasmids were totally or partially deleted. The prevalence of sulI and sulII could thus be accounted for by their stable integration in transposons and in plasmids that are widely disseminated among gram-negative bacteria.19911952855
446420.9999Class 1 integrons, gene cassettes, mobility, and epidemiology. Integrons are genetic elements that, although unable to move themselves, contain gene cassettes that can be mobilized to other integrons or to secondary sites in the bacterial genome. The majority of approximately 60 known gene cassettes encode resistance to antibiotics. Recently, a number of gene cassettes encoding extended-spectrum beta-lactamases or carbapenemases have been described. Up to at least five cassettes may be present in an integron, which leads to multiresistance. Frequently, more than one integron is observed within the same bacterial cell. Integrons are widespread in their species distribution. Although integrons are normally reported from Enterobacteriaceae and other gram-negative bacteria, an integron has been described in Corynebacterium glutamicum, a gram-positive species. The gene cassette in this integron showed even higher expression when compared to the expression in Escherichia coli. Integrons have been reported from all continents and are found frequently. The widespread occurrence of integrons is thought to be due to their association with transposon plasmids, conjugative plasmids, or both. Integrons form an important source for the spread of antibiotic resistance, at least in gram-negative bacteria but also potentially in gram-positive bacteria. The aim of this review is to describe the versatility of integrons, especially their mobility and their ability to collect resistance genes.199910614949
446830.9999Mobile gene cassettes and integrons: moving antibiotic resistance genes in gram-negative bacteria. In Gram-negative pathogens, multiple antibiotic resistance is common and many of the known resistance genes are contained in mobile gene cassettes. Cassettes can be integrated into or deleted from their receptor elements, the integrons, or infrequently may be integrated at other locations via site-specific recombination catalysed by an integron-encoded recombinase. As a consequence, arrays of several different antibiotic resistance genes can be created. Over 40 gene cassettes and three distinct classes of integrons have been identified to date. Cassette-associated genes conferring resistance to beta-lactams, aminoglycosides, trimethoprim, chloramphenicol, streptothricin and quaternary ammonium compounds used as antiseptics and disinfectants have been found. In addition, most members of the commonest family of integrons (class 1) include a sulfonamide resistance determinant in the backbone structure. Integrons are themselves translocatable, though most are defective transposon derivatives. Integron movement allows transfer of the cassette-associated resistance genes from one replicon to another or into another active transposon which facilitates spread of integrons that are transposition defective. Horizontal transfer of the resistance genes can be achieved when an integron containing one or more such genes is incorporated into a broad-host-range plasmid. Likewise, single cassettes integrated at secondary sites in a broad-host-range plasmid can also move across species boundaries.19979189642
446940.9999Integrons: an antibiotic resistance gene capture and expression system. Bacteria can transfer genetic information to provide themselves with protection against most antibiotics. The acquisition of resistance gene arrays involves genetic mobile elements like plasmids and transposons. Another class of genetic structures, termed integrons, have been described and contain one or more gene cassettes located at a specific site. Integrons are defined by an intl gene encoding an integrase, a recombination site attl and a strong promoter. At least six classes of integrons have been determined according to their intl gene. Classes 1, 2 and 3 are the most studied and are largely implicated in the dissemination of antibiotic resistance. A gene cassette includes an open reading frame and, at the 3'-end, a recombination site attC. Integration or excision of cassettes occur by a site-specific recombination mechanism catalyzed by the integrase. However, insertion can occur, albeit rarely, at non-specific sites leading to a stable situation for the cassette. Cassettes are transcribed from the common promoter located in the 5'-conserved segment and expression of distal genes is reduced by the presence of upstream cassettes. Most gene cassettes encode antibiotic resistant determinants but antiseptic resistant genes have also been described. Integrons seem to have a major role in the spread of multidrug resistance in gram-negative bacteria but integrons in gram-positive bacteria were described recently. Moreover, the finding of super-integrons with gene-cassettes coding for other determinants (biochemical functions, virulence factors) in Vibrio isolates dating from 1888 suggests the likely implication of this multicomponent cassette-integron system in bacterial genome evolution before the antibiotic era and to a greater extent than initially believed.200010987194
466050.9999Recovery of new integron classes from environmental DNA. Integrons are genetic elements known for their role in the acquisition and expression of genes conferring antibiotic resistance. Such acquisition is mediated by an integron-encoded integrase, which captures genes that are part of gene cassettes. To test whether integrons occur in environments with no known history of antibiotic exposure, PCR primers were designed to conserved regions of the integrase gene and the gene cassette recombination site. Amplicons generated from four environmental DNA samples contained features typical of the integrons found in antibiotic-resistant and pathogenic bacteria. The sequence diversity of the integrase genes in these clones was sufficient to classify them within three new classes of integron. Since they are derived from environments not associated with antibiotic use, integrons appear to be more prevalent in bacteria than previously observed.200111166996
446760.9999PCR mapping of integrons reveals several novel combinations of resistance genes. The integron is a new type of mobile element which has evolved by a site-specific recombinational mechanism. Integrons consist of two conserved segments of DNA separated by a variable region containing one or more genes integrated as cassettes. Oligonucleotide probes specific for the conserved segments have revealed that integrons are widespread in recently isolated clinical bacteria. Also, by using oligonucleotide probes for several antibiotic resistance genes, we have found novel combinations of resistance genes in these strains. By using PCR, we have determined the content and order of the resistance genes inserted between the conserved segments in the integrons of these clinical isolates. PCR mapping of integrons can be a useful epidemiological tool to study the evolution of multiresistance plasmids and transposons and dissemination of antibiotic resistance genes.19957695304
465870.9998Class 1 integrons potentially predating the association with tn402-like transposition genes are present in a sediment microbial community. Integrons are genetic elements that contribute to lateral gene transfer in bacteria as a consequence of possessing a site-specific recombination system. This system facilitates the spread of genes when they are part of mobile cassettes. Most integrons are contained within chromosomes and are confined to specific bacterial lineages. However, this is not the case for class 1 integrons, which were the first to be identified and are one of the single biggest contributors to multidrug-resistant nosocomial infections, carrying resistance to many antibiotics in diverse pathogens on a global scale. The rapid spread of class 1 integrons in the last 60 years is partly a result of their association with a specific suite of transposition functions, which has facilitated their recruitment by plasmids and other transposons. The widespread use of antibiotics has acted as a positive selection pressure for bacteria, especially pathogens, which harbor class 1 integrons and their associated antibiotic resistance genes. Here, we have isolated bacteria from soil and sediment in the absence of antibiotic selection. Class 1 integrons were recovered from four different bacterial species not known to be human pathogens or commensals. All four integrons lacked the transposition genes previously considered to be a characteristic of this class. At least two of these integrons were located on a chromosome, and none of them possessed antibiotic resistance genes. We conclude that novel class 1 integrons are present in a sediment environment in various bacteria of the beta-proteobacterial class. These data suggest that the dispersal of this class may have begun before the "antibiotic era."200616885440
452880.9998Study on the excision and integration mediated by class 1 integron in Streptococcus pneumoniae. As a novel antibiotic resistance mobile element, integron was recognized as a primary source of antibiotic genes among Gram-positive organisms for its excision and integration of exogenous genes. In this study, Streptococcus pneumoniae was subjected to investigate the excision and integration of class 1 integron with eight different plasmids. As the results indicated, excision in both att site and gene cassettes were successfully observed, which was further confirmed by integration assays and PCR amplification. The observation of class 1 integron mediated excision and integration of various exogenous antibiotics resistance genes may raise the attention of integrons as novel antibiotic resistance determinant in Gram-positive bacteria, especially in Streptococcus.201728923604
447790.9998Mechanisms of antibiotic resistance and their dissemination of resistance genes in the hospital environment. The dissemination of resistance determinants among bacterial populations depends on ecological and epidemiological properties as well as additional factors: 1) the mechanism of resistance or its specificity toward a certain drug, and 2) the genetic basis in relation to the mobility of the genetic material and its survival in bacteria. From two resistance mechanisms directed toward old-fashioned drugs, namely sulfonamides (Su) and streptomycin (Sm), we can deduce that a resistance mechanism is encoded by a special sort of genetic material. Thus the linked SmSu resistance mediated by a sulfonamide-resistant dihydropteroatsynthetase II and the aminoglycoside phosphotransferase APH-(3") is always located on very small pBP1-like plasmids. Such plasmids survive without selective pressure of drugs in Enterobacteriaceae in the bowel flora of humans and animals. Both resistance determinants can be mediated by a transposon which codes for the production of a dihydropteroatsynthetase I in connection with an aminoglycoside adenylyltransferase AAD-(3"). These two mechanisms are genetically linked as well. The basic structure is a transposon designated Tn2411, which belongs to a whole family of transposons, all including the basic structure; however, their genetic exchange and substitution leads to structures coding for many different enzymatic characters: ANT-(2") (Gentamicin resistance), CAT (Chloramphenicol resistance), AAC-(6') (resistance to all modern aminoglycosides), TEM-1, OXA-1, OXA-2, or PSE (beta-lactam resistance). Resistance to the modern beta-lactamase-stable antibiotics is mediated by mutation in the regulatory genes of chromosomally-determined beta-lactamases. A spread of these resistance mechanisms can be avoided as long as the responsible genes are not located on sufficient structures like small plasmids or efficient transposons.19836558024
4526100.9998The tetracycline resistance gene tet(M) exhibits mosaic structure. Tetracycline resistance genes of the M class, tet(M), are typically found on mobile genetic elements as the conjugative transposons of gram-positive bacteria. By comparing the sequences of eight different tet(M) genes (from Enterococcus faecalis, Streptococcus pneumoniae, Staphylococcus aureus, Ureaplasma urealyticum, and Neisseria), a mosaic structure was detected which could be traced to two distinct alleles. The two alleles displayed a divergence of 8% and a different G/C content. The block structure of these genes provides evidence for the contribution of homologous recombination to the evolution and the heterogeneity of the tet(M) locus. Unlike described cases of chromosomally located mosaic loci, tet(M) is a relatively recently acquired determinant in the species examined and it would appear that mosaic structure within tet(M) has evolved after acquisition of the gene by the mobile genetic elements upon which it is located.19968812782
4527110.9998Study on the excision and integration mediated by class 1 integron in Enterococcus faecalis. Recognized as a mobile genetic element, integron is correlated to the excision and integration of exogenous genes, especially bacterial resistance genes. However, most of the investigations focused on Gram-positive bacteria with few exceptions. In this study, Enterococcus faecalis was selected to investigate the excision and integration of class 1 integron. A total of eight plasmids were subjected to establish the transformants for excision and integration test. As results showed, positive excision assay was observed, which had been confirmed by the further integration assays and PCR amplification. The observation of class 1 integron mediated excision and integration of various exogenous antibiotics resistance genes should raise the attention of integrons as novel antibiotic resistance determinant in Gram-positive bacteria, especially in Enterococcus.201728390978
9889120.9998Evolution and dissemination of L and M plasmid lineages carrying antibiotic resistance genes in diverse Gram-negative bacteria. Conjugative, broad host-range plasmids of the L/M complex have been associated with antibiotic resistance since the 1970s. They are found in Gram-negative bacterial genera that cause human infections and persist in hospital environments. It is crucial that these plasmids are typed accurately so that their clinical and global dissemination can be traced in epidemiological studies. The L/M complex has previously been divided into L, M1 and M2 subtypes. However, those types do not encompass all diversity seen in the group. Here, we have examined 148 complete L/M plasmid sequences in order to understand the diversity of the complex and trace the evolution of distinct lineages. The backbone sequence of each plasmid was determined by removing translocatable genetic elements and reversing their effects in silico. The sequence identities of replication regions and complete backbones were then considered for typing. This supported the distinction of L and M plasmids and revealed that there are five L and eight M types, where each type is comprised of further sub-lineages that are distinguished by variation in their backbone and translocatable element content. Regions containing antibiotic resistance genes in L and M sub-lineages have often formed by initial rare insertion events, followed by insertion of other translocatable elements within the inceptive element. As such, islands evolve in situ to contain genes conferring resistance to multiple antibiotics. In some cases, different plasmid sub-lineages have acquired the same or related resistance genes independently. This highlights the importance of these plasmids in acting as vehicles for the dissemination of emerging resistance genes. Materials are provided here for typing plasmids of the L/M complex from complete sequences or draft genomes. This should enable rapid identification of novel types and facilitate tracking the evolution of existing lineages.202132781088
4522130.9998Involvement of aph(3')-IIa in the formation of mosaic aminoglycoside resistance genes in natural environments. Intragenic recombination leading to mosaic gene formation is known to alter resistance profiles for particular genes and bacterial species. Few studies have examined to what extent aminoglycoside resistance genes undergo intragenic recombination. We screened the GenBank database for mosaic gene formation in homologs of the aph(3')-IIa (nptII) gene. APH(3')-IIa inactivates important aminoglycoside antibiotics. The gene is widely used as a selectable marker in biotechnology and enters the environment via laboratory discharges and the release of transgenic organisms. Such releases may provide opportunities for recombination in competent environmental bacteria. The retrieved GenBank sequences were grouped in three datasets comprising river water samples, duck pathogens and full-length variants from various bacterial genomes and plasmids. Analysis for recombination in these datasets was performed with the Recombination Detection Program (RDP4), and the Genetic Algorithm for Recombination Detection (GARD). From a total of 89 homologous sequences, 83% showed 99-100% sequence identity with aph(3')-IIa originally described as part of transposon Tn5. Fifty one were unique sequence variants eligible for recombination analysis. Only a single recombination event was identified with high confidence and indicated the involvement of aph(3')-IIa in the formation of a mosaic gene located on a plasmid of environmental origin in the multi-resistant isolate Pseudomonas aeruginosa PA96. The available data suggest that aph(3')-IIa is not an archetypical mosaic gene as the divergence between the described sequence variants and the number of detectable recombination events is low. This is in contrast to the numerous mosaic alleles reported for certain penicillin or tetracycline resistance determinants.201526042098
9888140.9998Evolution and typing of IncC plasmids contributing to antibiotic resistance in Gram-negative bacteria. The large, broad host range IncC plasmids are important contributors to the spread of key antibiotic resistance genes and over 200 complete sequences of IncC plasmids have been reported. To track the spread of these plasmids accurate typing to identify the closest relatives is needed. However, typing can be complicated by the high variability in resistance gene content and various typing methods that rely on features of the conserved backbone have been developed. Plasmids can be broadly typed into two groups, type 1 and type 2, using four features that differentiate the otherwise closely related backbones. These types are found in many different countries in bacteria from humans and animals. However, hybrids of type 1 and type 2 are also occasionally seen, and two further types, each represented by a single plasmid, were distinguished. Generally, the antibiotic resistance genes are located within a small number of resistance islands, only one of which, ARI-B, is found in both type 1 and type 2. The introduction of each resistance island generates a new lineage and, though they are continuously evolving via the loss of resistance genes or introduction of new ones, the island positions serve as valuable lineage-specific markers. A current type 2 lineage of plasmids is derived from an early type 2 plasmid but the sequences of early type 1 plasmids include features not seen in more recent type 1 plasmids, indicating a shared ancestor rather than a direct lineal relationship. Some features, including ones essential for maintenance or for conjugation, have been examined experimentally.201830081066
4604150.9998Dissemination of the strA-strB streptomycin-resistance genes among commensal and pathogenic bacteria from humans, animals, and plants. Gene transfer within bacterial communities has been recognized as a major contributor in the recent evolution of antibiotic resistance on a global scale. The linked strA-strB genes, which encode streptomycin-inactivating enzymes, are distributed worldwide and confer streptomycin resistance in at least 17 genera of gram-negative bacteria. Nucleotide sequence analyses suggest that strA-strB have been recently disseminated. In bacterial isolates from humans and animals, strA-strB are often linked with the suIII sulfonamide-resistance gene and are encoded on broad-host-range nonconjugative plasmids. In bacterial isolates from plants, strA-strB are encoded on the Tn3-type transposon Tn5393 which is generally borne on conjugative plasmids. The wide distribution of the strA-strB genes in the environment suggests that gene transfer events between human, animal, and plant-associated bacteria have occurred. Although the usage of streptomycin in clinical medicine and animal husbandry has diminished, the persistence of strA-strB in bacterial populations implies that factors other than direct antibiotic selection are involved in maintenance of these genes.19969147689
4659160.9998Evidence for dynamic exchange of qac gene cassettes between class 1 integrons and other integrons in freshwater biofilms. Class 1 integrons carried by pathogens have acquired over 100 different gene cassettes encoding resistance to antimicrobial compounds, helping to generate a crisis in the management of infectious disease. It is presumed that these cassettes originated from environmental bacteria, but exchange of gene cassettes has surprisingly never been demonstrated outside laboratory or clinical contexts. We aimed to identify a natural environment where such exchanges might occur, and determine the phylogenetic range of participating integrons. Here we examine freshwater biofilms and show that families of cassettes conferring resistance to quaternary ammonium compounds (qac) are found on class 1 integrons identical to those from clinical contexts, on sequence variants of class 1 integrons only known from natural environments, and on other diverse classes of integrons only known from the chromosomes of soil and freshwater Proteobacteria. We conclude that gene cassettes might be readily shared between different integron classes found in environmental, commensal and pathogenic bacteria. This suggests that class 1 integrons in pathogens have access to a vast pool of gene cassettes, any of which could confer a phenotype of clinical relevance. Exploration of this resource might allow identification of resistance or virulence genes before they become part of multi-drug-resistant human pathogens.200919459951
4523170.9998Mosaic structure of a multiple-drug-resistant, conjugative plasmid from Campylobacter jejuni. Partial sequence analysis of a tet(O) plasmid from a multiple-drug-resistant clinical isolate of Campylobacter jejuni revealed 10 genes or pseudogenes encoding different aminoglycoside inactivating enzymes, transposase-like genes, and multiple unknown genes from a variety of pathogenic and commensal bacteria. The plasmid could be mobilized by a P incompatibility group plasmid into Escherichia coli, where it apparently integrated into the chromosome and expressed high-level resistance to multiple aminoglycoside antibiotics. This work provides new information about both the nature of drug resistance in C. jejuni and the ability of C. jejuni to exchange genes with other bacterial species.200515917546
4473180.9998The genetics of bacterial trimethoprim resistance in tropical areas. Resistance to trimethoprim in Gram-negative bacteria is largely manifested by two trimethoprim resistant dihydrofolate reductases (types I and II) encoded by genes originally located on resistance plasmids. Although trimethoprim resistance increased markedly after the clinical introduction of trimethoprim in the West, its spread has slowed and, in Edinburgh at least, has actually been declining. This reduction has been accompanied by the migration of a transposon, encoding the type I plasmid resistance gene, into the bacterial chromosome. In tropical areas, the incidence of trimethoprim resistance is very much higher. In Tanzania, it has spilled over into other bacteria outside the Enterobacteriaceae, but it was in India where the major problem existed. The majority (64%) of the Indian Enterobacteriaceae studied were resistant to the drug and most of the resistance genes were located on very large plasmids which also conferred resistance to many other antibacterial drugs. Some Indian plasmids carried a new trimethoprim resistance gene which is not detectable by conventional sensitivity tests and may be spreading unnoticed elsewhere. The proportion of trimethoprim resistance has been related to the volume of antibacterial drugs used.19873318025
9973190.9998Spread and Persistence of Virulence and Antibiotic Resistance Genes: A Ride on the F Plasmid Conjugation Module. The F plasmid or F-factor is a large, 100-kbp, circular conjugative plasmid of Escherichia coli and was originally described as a vector for horizontal gene transfer and gene recombination in the late 1940s. Since then, F and related F-like plasmids have served as role models for bacterial conjugation. At present, more than 200 different F-like plasmids with highly related DNA transfer genes, including those for the assembly of a type IV secretion apparatus, are completely sequenced. They belong to the phylogenetically related MOB(F12)A group. F-like plasmids are present in enterobacterial hosts isolated from clinical as well as environmental samples all over the world. As conjugative plasmids, F-like plasmids carry genetic modules enabling plasmid replication, stable maintenance, and DNA transfer. In this plasmid backbone of approximately 60 kbp, the DNA transfer genes occupy the largest and mostly conserved part. Subgroups of MOB(F12)A plasmids can be defined based on the similarity of TraJ, a protein required for DNA transfer gene expression. In addition, F-like plasmids harbor accessory cargo genes, frequently embedded within transposons and/or integrons, which harness their host bacteria with antibiotic resistance and virulence genes, causing increasingly severe problems for the treatment of infectious diseases. Here, I focus on key genetic elements and their encoded proteins present on the F-factor and other typical F-like plasmids belonging to the MOB(F12)A group of conjugative plasmids.201830022749