# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 9872 | 0 | 0.9943 | pCTX-M3-Structure, Function, and Evolution of a Multi-Resistance Conjugative Plasmid of a Broad Recipient Range. pCTX-M3 is the archetypic member of the IncM incompatibility group of conjugative plasmids (recently referred to as IncM2). It is responsible for the worldwide dissemination of numerous antibiotic resistance genes, including those coding for extended-spectrum β-lactamases and conferring resistance to aminoglycosides. The IncM plasmids acquired during evolution diverse mobile genetic elements found in one or two multiple resistance regions, MRR(s), grouping antibiotic resistance genes as well as mobile genetic elements or their remnants. The IncM plasmids can be found in bacteria inhabiting various environments. The information on the structure and biology of pCTX-M3 is integrated in this review. It focuses on the functional modules of pCTX-M3 responsible for its replication, stable maintenance, and conjugative transfer, indicating that the host range of the pCTX-M3 replicon is limited to representatives of the family Enterobacteriaceae (Enterobacterales ord. nov.), while the range of recipients of its conjugation system is wide, comprising Alpha-, Beta-, and Gammaproteobacteria, and also Firmicutes. | 2021 | 33925677 |
| 9855 | 1 | 0.9941 | Conjugative IncC Plasmid Entry Triggers the SOS Response and Promotes Effective Transfer of the Integrative Antibiotic Resistance Element SGI1. The broad-host-range IncC plasmid family and the integrative mobilizable Salmonella genomic island 1 (SGI1) and its derivatives enable the spread of medically important antibiotic resistance genes among Gram-negative pathogens. Although several aspects of the complex functional interactions between IncC plasmids and SGI1 have been recently deciphered regarding their conjugative transfer and incompatibility, the biological signal resulting in the hijacking of the conjugative plasmid by the integrative mobilizable element remains unknown. Here, we demonstrate that the conjugative entry of IncC/IncA plasmids is detected at an early stage by SGI1 through the transient activation of the SOS response, which induces the expression of the SGI1 master activators SgaDC, shown to play a crucial role in the complex biology between SGI1 and IncC plasmids. Besides, we developed an original tripartite conjugation approach to directly monitor SGI1 mobilization in a time-dependent manner following conjugative entry of IncC plasmids. Finally, we propose an updated biological model of the conjugative mobilization of the chromosomal resistance element SGI1 by IncC plasmids. IMPORTANCE Antimicrobial resistance has become a major public health issue, particularly with the increase of multidrug resistance (MDR) in both animal and human pathogenic bacteria and with the emergence of resistance to medically important antibiotics. The spread between bacteria of successful mobile genetic elements, such as conjugative plasmids and integrative elements conferring multidrug resistance, is the main driving force in the dissemination of acquired antibiotic resistances among Gram-negative bacteria. Broad-host-range IncC plasmids and their integrative mobilizable SGI1 counterparts contribute to the spread of critically important resistance genes (e.g., extended-spectrum β-lactamases [ESBLs] and carbapenemases). A better knowledge of the complex biology of these broad-host-range mobile elements will help us to understand the dissemination of antimicrobial resistance genes that occurred across Gammaproteobacteria borders. | 2023 | 36472437 |
| 9843 | 2 | 0.9940 | Conjugative transposons: an unusual and diverse set of integrated gene transfer elements. Conjugative transposons are integrated DNA elements that excise themselves to form a covalently closed circular intermediate. This circular intermediate can either reintegrate in the same cell (intracellular transposition) or transfer by conjugation to a recipient and integrate into the recipient's genome (intercellular transposition). Conjugative transposons were first found in gram-positive cocci but are now known to be present in a variety of gram-positive and gram-negative bacteria also. Conjugative transposons have a surprisingly broad host range, and they probably contribute as much as plasmids to the spread of antibiotic resistance genes in some genera of disease-causing bacteria. Resistance genes need not be carried on the conjugative transposon to be transferred. Many conjugative transposons can mobilize coresident plasmids, and the Bacteroides conjugative transposons can even excise and mobilize unlinked integrated elements. The Bacteroides conjugative transposons are also unusual in that their transfer activities are regulated by tetracycline via a complex regulatory network. | 1995 | 8531886 |
| 9884 | 3 | 0.9939 | Incompatibility Group I1 (IncI1) Plasmids: Their Genetics, Biology, and Public Health Relevance. Bacterial plasmids are extrachromosomal genetic elements that often carry antimicrobial resistance (AMR) genes and genes encoding increased virulence and can be transmissible among bacteria by conjugation. One key group of plasmids is the incompatibility group I1 (IncI1) plasmids, which have been isolated from multiple Enterobacteriaceae of food animal origin and clinically ill human patients. The IncI group of plasmids were initially characterized due to their sensitivity to the filamentous bacteriophage If1. Two prototypical IncI1 plasmids, R64 and pColIb-P9, have been extensively studied, and the plasmids consist of unique regions associated with plasmid replication, plasmid stability/maintenance, transfer machinery apparatus, single-stranded DNA transfer, and antimicrobial resistance. IncI1 plasmids are somewhat unique in that they encode two types of sex pili, a thick, rigid pilus necessary for mating and a thin, flexible pilus that helps stabilize bacteria for plasmid transfer in liquid environments. A key public health concern with IncI1 plasmids is their ability to carry antimicrobial resistance genes, including those associated with critically important antimicrobials used to treat severe cases of enteric infections, including the third-generation cephalosporins. Because of the potential importance of these plasmids, this review focuses on the distribution of the plasmids, their phenotypic characteristics associated with antimicrobial resistance and virulence, and their replication, maintenance, and transfer. | 2021 | 33910982 |
| 5030 | 4 | 0.9938 | Characterization of ESBL disseminating plasmids. Bacteria producing extended-spectrum β-lactamases (ESBLs) constitute a globally increasing problem that contributes to treatment complications and elevated death rates. The extremely successful dissemination by ESBL-producing Enterobacteriaceae during the latest decades is a result of the combination of mobilization, evolution and horizontal spread of β-lactamase genes on plasmids. In parallel, spread of these plasmids to particularly well-adapted bacterial clones (outbreak clones) has expanded. In this review we describe ESBL-producing bacteria and the genetic mechanisms for dissemination of ESBL resistance. We describe available methodology for studying plasmids and the importance of including plasmids in epidemiological typing as natural parts of the organisms. Plasmids play a fundamental role in how resistance arises and disseminates. | 2016 | 26135711 |
| 1876 | 5 | 0.9938 | Occurrence and Characteristics of Mobile Colistin Resistance (mcr) Gene-Containing Isolates from the Environment: A Review. The emergence and spread of mobile colistin (COL) resistance (mcr) genes jeopardize the efficacy of COL, a last resort antibiotic for treating deadly infections. COL has been used in livestock for decades globally. Bacteria have mobilized mcr genes (mcr-1 to mcr-9). Mcr-gene-containing bacteria (MGCB) have disseminated by horizontal/lateral transfer into diverse ecosystems, including aquatic, soil, botanical, wildlife, animal environment, and public places. The mcr-1, mcr-2, mcr-3, mcr-5, mcr-7, and mcr-8 have been detected in isolates from and/or directly in environmental samples. These genes are harboured by Escherichia coli, Enterobacter, Klebsiella, Proteus, Salmonella, Citrobacter, Pseudomonas, Acinetobacter, Kluyvera, Aeromonas, Providencia, and Raulotella isolates. Different conjugative and non-conjugative plasmids form the backbones for mcr in these isolates, but mcr have also been integrated into the chromosome of some strains. Insertion sequences (IS) (especially ISApl1) located upstream or downstream of mcr, class 1-3 integrons, and transposons are other drivers of mcr in the environment. Genes encoding multi-/extensive-drug resistance and virulence are often co-located with mcr on plasmids in environmental isolates. Transmission of mcr to/among environmental strains is clonally unrestricted. Contact with the mcr-containing reservoirs, consumption of contaminated animal-/plant-based foods or water, international animal-/plant-based food trades and travel, are routes for transmission of MGCB. | 2020 | 32041167 |
| 9819 | 6 | 0.9938 | Site-specific recombination and shuffling of resistance genes in transposon Tn21. Many multidrug-resistant transposons found in natural isolates of Gram-negative bacteria are close relatives of Tn21. Thus, the Tn21 subgroup of the Tn3 family of transposable elements is the most successful homogeneous group in acquiring resistance to newly introduced antibiotics. This paper summarizes the mode of acquisition of resistance genes by these elements. | 1991 | 1660178 |
| 9890 | 7 | 0.9938 | The origin and evolution of IncF33 plasmids based on large-scale data sets. Plasmids that capture multiple antibiotic resistance genes are spreading widely, leading to the emergence and prevalence of multidrug-resistant bacteria. IncF33 plasmids are a newly emerged plasmid type highly prevalent in animal-source Enterobacterales in China, and they are important vectors for transmitting several clinically important antibiotic resistance genes. The study revealed that the IncF33 plasmid is mainly prevalent in China animal-derived Escherichia coli and has the potential for cointegration and intercontinental dissemination. Therefore, it is crucial to enhance surveillance and control measures to limit the spread of IncF33 plasmids and their associated antibiotic resistance genes. | 2023 | 37750716 |
| 9946 | 8 | 0.9938 | Genomic insights into plasmid-mediated antimicrobial resistance in the bacterium Bhargavaea beijingensis strain PS04. The dissemination of antimicrobial-resistant bacteria through environment is a major health concern for public health. Pathogenic bacteria in natural environment can mediate the transfer of antimicrobial-resistant genes via horizontal gene transfer to naturally occurring bacteria in the soil. Bhargavaea beijingensis is a Gram-negative bacterium that is commonly found in soil and water. In recent years, there has been an emergence of antibiotic-resistant strains of environmental bacteria, which pose a significant threat to human health. One mechanism of antibiotic resistance in bacteria is through the acquisition of plasmids, which can carry genes that confer resistance to various antibiotics. In this study, a novel plasmid of repUS12 replicon type was identified in the strain PS04 of B. beijingensis, which carried the ermT and tet(L) genes, encoding resistance to macrolides, lincosamides, and tetracycline. The plasmid was found to be the first of its kind in B. beijingensis and was thought to have been acquired through horizontal gene transfer. The emergence of plasmid-mediated resistance in B. beijingensis highlights the need for continued surveillance and monitoring of antibiotic resistance in environmental bacteria. | 2023 | 38133813 |
| 4925 | 9 | 0.9937 | Assessing genetic diversity and similarity of 435 KPC-carrying plasmids. The global spread and diversification of multidrug-resistant Gram-negative (MRGN) bacteria poses major challenges to healthcare. In particular, carbapenem-resistant Klebsiella pneumoniae strains have been frequently identified in infections and hospital-wide outbreaks. The most frequently underlying resistance gene (bla(KPC)) has been spreading over the last decade in the health care setting. bla(KPC) seems to have rapidly diversified and has been found in various species and on different plasmid types. To review the progress and dynamics of this diversification, all currently available KPC plasmids in the NCBI database were analysed in this work. Plasmids were grouped into 257 different representative KPC plasmids, of which 79.4% could be clearly assigned to incompatibility (Inc) group or groups. In almost half of all representative plasmids, the KPC gene is located on Tn4401 variants, emphasizing the importance of this transposon type for the transmission of KPC genes to other plasmids. The transposons also seem to be responsible for the occurrence of altered or uncommon fused plasmid types probably due to incomplete transposition. Moreover, many KPC plasmids contain genes that encode proteins promoting recombinant processes and mutagenesis; in consequence accelerating the diversification of KPC genes and other colocalized resistance genes. | 2019 | 31375735 |
| 6615 | 10 | 0.9937 | Is Africa ready for mobile colistin resistance threat? Antimicrobial resistance is a growing public health problem and a threat to effective treatment and prevention of an array of infections caused by bacteria. Africa is already faced with many socio-economic and health crises. Many countries in Africa can seldom boast of a standardized health care facility comparable to those in developed countries. Yet, the non-therapeutic use of COL has been banned in developed countries. However, in Africa, except for South Africa, COL is an over-the-counter (OTC) medication sold and dispensed by non-professionals/without a veterinarian's supervision. The ban of non-therapeutic COL in developed countries has proven to reduce the development of mobile colistin resistance (MCR) in humans and animals. The unregulated use of COL has been proven to select pathogenic and commensal bacteria resistance. A transmissible plasmid-mediated colistin determinant, mobile COL resistance (mcr) gene, which is rapidly transferred/acquired horizontally or laterally intra/inter-species/genera, has been reported. A highly promiscuous mobile genetic element like plasmids containing transposons, insertion sequences, and integrons aid the carriage/rapid transfer and acquisition of these mcr genes. Hence, we highlight the danger posed by escalating colistin (COL) resistance in the continent and the impetus to halt the indiscriminate and non-therapeutic use of COL to protect public health. | 2021 | 34377360 |
| 9817 | 11 | 0.9937 | Common regions e.g. orf513 and antibiotic resistance: IS91-like elements evolving complex class 1 integrons. The ability of bacteria to procure, sometimes rearrange, and evince acquired DNA continues to impress us-even more so if this genetic plasticity involves the sequestering of antibiotic resistance genes. The acquisition of genes in bacteria is often facilitated by transposons, integrons and archetype insertion elements. Recently however, a new element, 'orf513', has been increasingly associated with class 1 integrons. Moreover, these 'complex' class 1 integrons can potentially mediate resistance to chloramphenicol, trimethoprim, aminoglycosides and tetracycline and may carry a range of beta-lactamase genes as well as the qnrA gene. Elements such as 'orf513' demonstrate IS91-like characteristics and will mobilize adjacent DNA via a process called rolling circle replication, and thus we have renamed them 'insertion sequence CRs' (ISCRs) to appropriately reflect their structure-function properties. In this article, we provide a brief description of these new and clinically important mobile elements, and how they are able to mobilize antibiotic resistance genes. | 2006 | 16751201 |
| 9818 | 12 | 0.9937 | ISCR elements: novel gene-capturing systems of the 21st century? "Common regions" (CRs), such as Orf513, are being increasingly linked to mega-antibiotic-resistant regions. While their overall nucleotide sequences show little identity to other mobile elements, amino acid alignments indicate that they possess the key motifs of IS91-like elements, which have been linked to the mobility ent plasmids in pathogenic Escherichia coli. Further inspection reveals that they possess an IS91-like origin of replication and termination sites (terIS), and therefore CRs probably transpose via a rolling-circle replication mechanism. Accordingly, in this review we have renamed CRs as ISCRs to give a more accurate reflection of their functional properties. The genetic context surrounding ISCRs indicates that they can procure 5' sequences via misreading of the cognate terIS, i.e., "unchecked transposition." Clinically, the most worrying aspect of ISCRs is that they are increasingly being linked with more potent examples of resistance, i.e., metallo-beta-lactamases in Pseudomonas aeruginosa and co-trimoxazole resistance in Stenotrophomonas maltophilia. Furthermore, if ISCR elements do move via "unchecked RC transposition," as has been speculated for ISCR1, then this mechanism provides antibiotic resistance genes with a highly mobile genetic vehicle that could greatly exceed the effects of previously reported mobile genetic mechanisms. It has been hypothesized that bacteria will surprise us by extending their "genetic construction kit" to procure and evince additional DNA and, therefore, antibiotic resistance genes. It appears that ISCR elements have now firmly established themselves within that regimen. | 2006 | 16760305 |
| 9929 | 13 | 0.9937 | Global dissemination of beta-lactamases mediating resistance to cephalosporins and carbapenems. While the main era of beta-lactam discovery programs is over, these agents continue to be the most widely prescribed antimicrobials in both community and hospital settings. This has led to considerable beta-lactam pressure on pathogens, resulting in a literal explosion of new beta-lactamase variants of existing enzyme classes. Recent advances in the molecular tools used to detect and characterize beta-lactamases and their genes has, in part, fueled the large increase in communications identifying novel beta-lactamases, particularly in Gram-negative bacilli. It now seems clear that the beta-lactams themselves have shaped the field of new enzymes, and the evolution of key amino acid substitutions around the active sites of beta-lactamases continues to drive resistance. Over 130 variants of TEM beta-lactamase now exist, and more are reported in the scientific literature each month. The most disturbing current trend is that many bla structural genes normally limited to the chromosome are now mobilized on plasmids and integrons, broadening the spread of resistance to include carbapenems and cephamycins. Furthermore, in some Enterobacteriaceae, concomitant loss of outer membrane porins act in concert with these transmissible beta-lactamase genes to confer resistance to the most potent beta-lactams and inhibitor combinations available. Continued reviews of the literature are necessary in order to keep abreast of the ingenuity with which bacteria are changing the current genetic landscape to confer resistance to this important class of antimicrobials. | 2004 | 15482196 |
| 5003 | 14 | 0.9937 | Updates on the global dissemination of colistin-resistant Escherichia coli: An emerging threat to public health. Colistin drug resistance is an emerging public health threat worldwide. The adaptability, existence and spread of colistin drug resistance in multiple reservoirs and ecological environmental settings is significantly increasing the rate of occurrence of multidrug resistant (MDR) bacteria such as Escherichia coli (E. coli). Here, we summarized the reports regarding molecular and biological characterization of mobile colistin resistance gene (mcr)-positive E. coli (MCRPEC), originating from diverse reservoirs, including but not limited to humans, environment, waste water treatment plants, wild, pets, and food producing animals. The MCRPEC revealed the abundance of clinically important resistance genes, which are responsible for MDR profile. A number of plasmid replicon types such as IncI2, IncX4, IncP, IncX, and IncFII with a predominance of IncI2 were facilitating the spread of colistin resistance. This study concludes the distribution of multiple sequence types of E. coli carrying mcr gene variants, which are possible threat to "One Health" perspective. In addition, we have briefly explained the newly known mechanisms of colistin resistance i.e. plasmid-encoded resistance determinant as well as presented the chromosomally-encoded resistance mechanisms. The transposition of ISApl1 into the chromosome and existence of intact Tn6330 are important for transmission and stability for mcr gene. Further, genetic environment of co-localized mcr gene with carbapenem-resistance or extended-spectrum β-lactamases genes has also been elaborated, which is limiting human beings to choose last resort antibiotics. Finally, environmental health and safety control measures along with spread mechanisms of mcr genes are discussed to avoid further propagation and environmental hazards of colistin resistance. | 2021 | 34364270 |
| 9964 | 15 | 0.9937 | Diversity and Global Distribution of IncL/M Plasmids Enabling Horizontal Dissemination of β-Lactam Resistance Genes among the Enterobacteriaceae. Antibiotic resistance determinants are frequently associated with plasmids and other mobile genetic elements, which simplifies their horizontal transmission. Several groups of plasmids (including replicons of the IncL/M incompatibility group) were found to play an important role in the dissemination of resistance genes encoding β-lactamases. The IncL/M plasmids are large, broad host range, and self-transmissible replicons. We have identified and characterized two novel members of this group: pARM26 (isolated from bacteria inhabiting activated sludge from a wastewater treatment plant) and pIGT15 (originating from a clinical strain of Escherichia coli). This instigated a detailed comparative analysis of all available sequences of IncL/M plasmids encoding β-lactamases. The core genome of these plasmids is comprised of 20 genes with conserved synteny. Phylogenetic analyses of these core genes allowed clustering of the plasmids into four separate groups, which reflect their antibiotic resistance profiles. Examination of the biogeography of the IncL/M plasmids revealed that they are most frequently found in bacteria of the family Enterobacteriaceae originating from the Mediterranean region and Western Europe and that they are able to persist in various ecological niches even in the absence of direct antibiotic selection pressure. | 2015 | 26236726 |
| 9960 | 16 | 0.9936 | Integrons, transposons and IS elements promote diversification of multidrug resistance plasmids and adaptation of their hosts to antibiotic pollutants from pharmaceutical companies. Plasmids are important vehicles for the dissemination of antibiotic resistance genes (ARGs) among bacteria by conjugation. Here, we determined the complete nucleotide sequences of nine different plasmids previously obtained by exogenous plasmid isolation from river and creek sediments and wastewater from a pharmaceutical company. We identified six IncP/P-1ε plasmids and single members of IncL, IncN and IncFII-like plasmids. Genetic structures of the accessory regions of the IncP/P-1ε plasmids obtained implied that multiple insertions and deletions had occurred, mediated by different transposons and Class 1 integrons with various ARGs. Our study provides compelling evidence that Class 1 integrons, Tn402-like transposons, Tn3-like transposons and/or IS26 played important roles in the acquisition of ARGs across all investigated plasmids. Our plasmid sequencing data provide new insights into how these mobile genetic elements could mediate the acquisition and spread of ARGs in environmental bacteria. | 2023 | 37655671 |
| 1533 | 17 | 0.9936 | A Transferable IncC-IncX3 Hybrid Plasmid Cocarrying bla(NDM-4), tet(X), and tmexCD3-toprJ3 Confers Resistance to Carbapenem and Tigecycline. Tigecycline is a last-resort antimicrobial against carbapenemase-producing Enterobacterales (CPE). However, mobile tigecycline resistance genes, tet(X) and tmexCD-toprJ, have emerged in China and have spread possibly worldwide. Tet(X) family proteins function as tigecycline-inactivating enzymes, and TMexCD-TOprJ complexes function as efflux pumps for tigecycline. Here, to the best of our knowledge we report a CPE isolate harboring both emerging tigecycline resistance factors for the first time. A carbapenem- and tigecycline-resistant Klebsiella aerogenes strain, NUITM-VK5, was isolated from an urban drainage in Vietnam in 2021, and a plasmid, pNUITM-VK5_mdr, cocarrying tet(X) and tmexCD3-toprJ3 along with the carbapenemase gene bla(NDM-4) was identified in NUITM-VK5. pNUITM-VK5_mdr was transferred to Escherichia coli by conjugation and simultaneously conferred high-level resistance against multiple antimicrobials, including carbapenems and tigecycline. An efflux pump inhibitor reduced TMexCD3-TOprJ3-mediated tigecycline resistance, suggesting that both tigecycline resistance factors independently and additively contribute to the high-level resistance. The plasmid had the IncX3 and IncC replicons and was estimated to be a hybrid of plasmids with different backbones. Unlike IncX3 plasmids, IncC plasmids are stably maintained in an extremely broad range of bacterial hosts in humans, animals, and the environment. Thus, the future global spread of multidrug resistance plasmids such as pNUITM-VK5_mdr poses a public health crisis. IMPORTANCE Tigecycline is important as a last-resort antimicrobial and effective against antimicrobial-resistant bacteria, such as carbapenem-producing Enterobacterales (CPE), whose infections are difficult to treat with antimicrobials. Since 2019, mobile tigecycline resistance genes, tet(X) and tmexCD-toprJ, and their variants have been reported mainly from China, and it has become important to understand their epidemiological situation and detailed genetic mechanisms. In this study, we identified a bacterial isolate coharboring tet(X) and tmexCD-toprJ on the same plasmid. A Klebsiella aerogenes isolate in Vietnam carried both these tigecycline resistance genes on a transferable plasmid leading to high-level resistance to multiple clinically important antimicrobials, including carbapenem and tigecycline, and could actually transfer the plasmid to other bacteria. The spread of such a multidrug resistance plasmid among bacterial pathogens should be of great concern because there are few antimicrobials to combat bacteria that have acquired the plasmid. | 2021 | 34346701 |
| 3009 | 18 | 0.9936 | Identification of a novel conjugative plasmid carrying the multiresistance gene cfr in Proteus vulgaris isolated from swine origin in China. The multiresistance gene cfr has a broad host range encompassing both Gram-positive and Gram-negative bacteria, and can be located on the chromosomes or on plasmids. In this study, a novel conjugative plasmid carrying cfr, designated as pPvSC3, was characterized in a Proteus vulgaris strain isolated from swine in China. Plasmid pPvSC3 is 284,528 bp in size and harbors 10 other antimicrobial resistance genes, making it a novel plasmid that differs from all known plasmids due to its unique backbone and repA gene. BLAST analysis of the plasmid sequence shows no significant homology to any known plasmid backbone, but shows high level homology to Providencia rettgeri strain CCBH11880 Contig_9, a strain isolated from surgical wound in Brazil, 2014. There are two resistance-determining regions in pPvSC3, a cfr-containing region and a multidrug-resistant (MDR) region. The cfr-containing region is flanked by IS26, which could be looped out via IS26-mediated recombination. The MDR region harbors 10 antimicrobial resistance genes carried by various DNA segments that originated from various sources. Plasmid pPvSC3 could be successfully transferred to Escherichia coli by conjugation. In summary, we have characterized a novel conjugative plasmid pPvSC3 carrying the multiresistance gene cfr and 10 other antimicrobial resistance genes, and consider that this novel type of plasmid deserves attention. | 2019 | 31499097 |
| 9894 | 19 | 0.9936 | Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids. The dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content) of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE) from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance. IMPORTANCE: The spread of antibiotic resistance among Gram-negative bacteria is a serious public health threat, as it can critically limit the types of drugs that can be used to treat infected patients. In particular, carbapenem-resistant members of the Enterobacteriaceae family are responsible for a significant and growing burden of morbidity and mortality. Here, we report on the mechanisms underlying the evolution of several plasmids carried by previously sequenced clinical Enterobacteriaceae isolates from the National Institutes of Health Clinical Center (NIH CC). Our ability to track genetic rearrangements that occurred within resistance plasmids was dependent on accurate annotation of the mobile genetic elements within the plasmids, which was greatly aided by access to long-read DNA sequencing data and knowledge of their mechanisms. Mobile genetic elements such as transposons and integrons have been strongly associated with the rapid spread of genes responsible for antibiotic resistance. Understanding the consequences of their actions allowed us to establish unambiguous evolutionary relationships between plasmids in the analysis set. | 2016 | 27923922 |