In situ, in vivo, and in vitro approaches for studying AMR plasmid conjugation in the gut microbiome. - Related Documents




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409901.0000In situ, in vivo, and in vitro approaches for studying AMR plasmid conjugation in the gut microbiome. Antimicrobial resistance (AMR) is a global threat, with evolution and spread of resistance to frontline antibiotics outpacing the development of novel treatments. The spread of AMR is perpetuated by transfer of antimicrobial resistance genes (ARGs) between bacteria, notably those encoded by conjugative plasmids. The human gut microbiome is a known 'melting pot' for plasmid conjugation, with ARG transfer in this environment widely documented. There is a need to better understand the factors affecting the incidence of these transfer events, and to investigate methods of potentially counteracting the spread of ARGs. This review describes the use and potential of three approaches to studying conjugation in the human gut: observation of in situ events in hospitalized patients, modelling of the microbiome in vivo predominantly in rodent models, and the use of in vitro models of various complexities. Each has brought unique insights to our understanding of conjugation in the gut. The use and development of these systems, and combinations thereof, will be pivotal in better understanding the significance, prevalence, and manipulability of horizontal gene transfer in the gut microbiome.202336341518
410010.9999Mathematical modelling to study the horizontal transfer of antimicrobial resistance genes in bacteria: current state of the field and recommendations. Antimicrobial resistance (AMR) is one of the greatest public health challenges we are currently facing. To develop effective interventions against this, it is essential to understand the processes behind the spread of AMR. These are partly dependent on the dynamics of horizontal transfer of resistance genes between bacteria, which can occur by conjugation (direct contact), transformation (uptake from the environment) or transduction (mediated by bacteriophages). Mathematical modelling is a powerful tool to investigate the dynamics of AMR; however, the extent of its use to study the horizontal transfer of AMR genes is currently unclear. In this systematic review, we searched for mathematical modelling studies that focused on horizontal transfer of AMR genes. We compared their aims and methods using a list of predetermined criteria and used our results to assess the current state of this research field. Of the 43 studies we identified, most focused on the transfer of single genes by conjugation in Escherichia coli in culture and its impact on the bacterial evolutionary dynamics. Our findings highlight the existence of an important research gap in the dynamics of transformation and transduction and the overall public health implications of horizontal transfer of AMR genes. To further develop this field and improve our ability to control AMR, it is essential that we clarify the structural complexity required to study the dynamics of horizontal gene transfer, which will require cooperation between microbiologists and modellers.201931409239
402820.9999Horizontal transfer of antibiotic resistance genes in the human gut microbiome. Infections caused by antibiotic-resistant bacteria are a major threat to public health. The pathogens causing these infections can acquire antibiotic resistance genes in a process termed horizontal gene transfer (HGT). HGT is a common event in the human gut microbiome, that is, the microbial ecosystem of the human intestinal tract. HGT in the gut microbiome can occur via different mechanisms of which transduction and conjugation have been best characterised. Novel bioinformatic tools and experimental approaches have been developed to determine the association of antibiotic resistance genes with their microbial hosts and to quantify the extent of HGT in the gut microbiome. Insights from studies into HGT in the gut microbiome may lead to the development of novel interventions to minimise the spread of antibiotic resistance genes among commensals and opportunistic pathogens.202032143027
402730.9999Good microbes, bad genes? The dissemination of antimicrobial resistance in the human microbiome. A global rise in antimicrobial resistance among pathogenic bacteria has proved to be a major public health threat, with the rate of multidrug-resistant bacterial infections increasing over time. The gut microbiome has been studied as a reservoir of antibiotic resistance genes (ARGs) that can be transferred to bacterial pathogens via horizontal gene transfer (HGT) of conjugative plasmids and mobile genetic elements (the gut resistome). Advances in metagenomic sequencing have facilitated the identification of resistome modulators, including live microbial therapeutics such as probiotics and fecal microbiome transplantation that can either expand or reduce the abundances of ARG-carrying bacteria in the gut. While many different gut microbes encode for ARGs, they are not uniformly distributed across, or transmitted by, various members of the microbiome, and not all are of equal clinical relevance. Both experimental and theoretical approaches in microbial ecology have been applied to understand differing frequencies of ARG horizontal transfer between commensal microbes as well as between commensals and pathogens. In this commentary, we assess the evidence for the role of commensal gut microbes in encoding antimicrobial resistance genes, the degree to which they are shared both with other commensals and with pathogens, and the host and environmental factors that can impact resistome dynamics. We further discuss novel sequencing-based approaches for identifying ARGs and predicting future transfer events of clinically relevant ARGs from commensals to pathogens.202235332832
400740.9999Detecting horizontal gene transfer among microbiota: an innovative pipeline for identifying co-shared genes within the mobilome through advanced comparative analysis. Horizontal gene transfer (HGT) is a key driver in the evolution of bacterial genomes. The acquisition of genes mediated by HGT may enable bacteria to adapt to ever-changing environmental conditions. Long-term application of antibiotics in intensive agriculture is associated with the dissemination of antibiotic resistance genes among bacteria with the consequences causing public health concern. Commensal farm-animal-associated gut microbiota are considered the reservoir of the resistance genes. Therefore, in this study, we identified known and not-yet characterized mobilized genes originating from chicken and porcine fecal samples using our innovative pipeline followed by network analysis to provide appropriate visualization to support proper interpretation.202438099617
407350.9999The Spread of Antibiotic Resistance Genes In Vivo Model. Infections caused by antibiotic-resistant bacteria are a major public health threat. The emergence and spread of antibiotic resistance genes (ARGs) in the environment or clinical setting pose a serious threat to human and animal health worldwide. Horizontal gene transfer (HGT) of ARGs is one of the main reasons for the dissemination of antibiotic resistance in vitro and in vivo environments. There is a consensus on the role of mobile genetic elements (MGEs) in the spread of bacterial resistance. Most drug resistance genes are located on plasmids, and the spread of drug resistance genes among microorganisms through plasmid-mediated conjugation transfer is the most common and effective way for the spread of multidrug resistance. Experimental studies of the processes driving the spread of antibiotic resistance have focused on simple in vitro model systems, but the current in vitro protocols might not correctly reflect the HGT of antibiotic resistance genes in realistic conditions. This calls for better models of how resistance genes transfer and disseminate in vivo. The in vivo model can better mimic the situation that occurs in patients, helping study the situation in more detail. This is crucial to develop innovative strategies to curtail the spread of antibiotic resistance genes in the future. This review aims to give an overview of the mechanisms of the spread of antibiotic resistance genes and then demonstrate the spread of antibiotic resistance genes in the in vivo model. Finally, we discuss the challenges in controlling the spread of antibiotic resistance genes and their potential solutions.202235898691
410260.9999Forces shaping the antibiotic resistome. Antibiotic resistance has become a problem of global scale. Resistance arises through mutation or through the acquisition of resistance gene(s) from other bacteria in a process called horizontal gene transfer (HGT). While HGT is recognized as an important factor in the dissemination of resistance genes in clinical pathogens, its role in the environment has been called into question by a recent study published in Nature. The authors found little evidence of HGT in soil using a culture-independent functional metagenomics approach, which is in contrast to previous work from the same lab showing HGT between the environment and human microbiome. While surprising at face value, these results may be explained by the lack of selective pressure in the environment studied. Importantly, this work suggests the need for careful monitoring of environmental antibiotic pollution and stringent antibiotic stewardship in the fight against resistance.201425213620
410170.9999What Is the Role of the Environment in the Emergence of Novel Antibiotic Resistance Genes? A Modeling Approach. It is generally accepted that intervention strategies to curb antibiotic resistance cannot solely focus on human and veterinary medicine but must also consider environmental settings. While the environment clearly has a role in transmission of resistant bacteria, its role in the emergence of novel antibiotic resistance genes (ARGs) is less clear. It has been suggested that the environment constitutes an enormous recruitment ground for ARGs to pathogens, but its extent is practically unknown. We have constructed a model framework for resistance emergence and used available quantitative data on relevant processes to identify limiting steps in the appearance of ARGs in human pathogens. We found that in a majority of possible scenarios, the environment would only play a minor role in the emergence of novel ARGs. However, the uncertainty is enormous, highlighting an urgent need for more quantitative data. Specifically, more data is most needed on the fitness costs of ARG carriage, the degree of dispersal of resistant bacteria from the environment to humans, and the rates of mobilization and horizontal transfer of ARGs. This type of data is instrumental to determine which processes should be targeted for interventions to curb development and transmission of ARGs in the environment.202134792330
402680.9999Gut microbiome in the emergence of antibiotic-resistant bacterial pathogens. The human gastrointestinal tract is home to a complex and dynamic community of microorganisms known as gut microbiota, which provide the host with important metabolic, signaling, and immunomodulatory functions. Both the commensal and pathogenic members of the gut microbiome serve as reservoirs of antimicrobial-resistance genes (ARG), which can cause potential health threats to the host and can transfer the ARGs to the susceptible microbes and into the environment. Antimicrobial resistance is becoming a major burden on human health and is widely recognized as a global challenge. The diversity and abundance of ARGs in the gut microbiome are variable and depend on the exposure to healthcare-associated antibiotics, usage of antibiotics in veterinary and agriculture, and the migration of the population. The transfer frequency of the ARGs through horizontal gene transfer (HGT) with the help of mobile genetic elements (MGEs) like plasmids, transposons, or phages is much higher among bacteria living in the GI tract compared to other microbial ecosystems. HGT in gut bacteria is facilitated through multiple gene transfer mechanisms, including transformation, conjugation, transduction, and vesicle fusion. It is the need of the hour to implement strict policies to limit indiscriminate antibiotic usage when needed. Developing rapid diagnostic tests for resistance determination and alternatives to antibiotics like vaccination, probiotics, and bacteriophage therapy should have the highest priority in the research and development sectors. Collective actions for sustainable development against resistant pathogens by promoting endogenous gut microbial growth and diversity through interdisciplinary research and findings are key to overcoming the current antimicrobial resistance crisis.202236280316
407090.9999Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens. Emergence of antibiotic resistant pathogenic bacteria poses a serious public health challenge worldwide. However, antibiotic resistance genes are not confined to the clinic; instead they are widely prevalent in different bacterial populations in the environment. Therefore, to understand development of antibiotic resistance in pathogens, we need to consider important reservoirs of resistance genes, which may include determinants that confer self-resistance in antibiotic producing soil bacteria and genes encoding intrinsic resistance mechanisms present in all or most non-producer environmental bacteria. While the presence of resistance determinants in soil and environmental bacteria does not pose a threat to human health, their mobilization to new hosts and their expression under different contexts, for example their transfer to plasmids and integrons in pathogenic bacteria, can translate into a problem of huge proportions, as discussed in this review. Selective pressure brought about by human activities further results in enrichment of such determinants in bacterial populations. Thus, there is an urgent need to understand distribution of resistance determinants in bacterial populations, elucidate resistance mechanisms, and determine environmental factors that promote their dissemination. This comprehensive review describes the major known self-resistance mechanisms found in producer soil bacteria of the genus Streptomyces and explores the relationships between resistance determinants found in producer soil bacteria, non-producer environmental bacteria, and clinical isolates. Specific examples highlighting potential pathways by which pathogenic clinical isolates might acquire these resistance determinants from soil and environmental bacteria are also discussed. Overall, this article provides a conceptual framework for understanding the complexity of the problem of emergence of antibiotic resistance in the clinic. Availability of such knowledge will allow researchers to build models for dissemination of resistance genes and for developing interventions to prevent recruitment of additional or novel genes into pathogens.201830555448
4004100.9999Diverse Distribution of Resistomes in the Human and Environmental Microbiomes. The routine therapeutic use of antibiotics has caused resistance genes to be disseminated across microbial populations. In particular, bacterial strains having antibiotic resistance genes are frequently observed in the human microbiome. Moreover, multidrug-resistant pathogens are now widely spread, threatening public health. Such genes are transferred and spread among bacteria even in different environments. Advances in high throughput sequencing technology and computational algorithms have accelerated investigation into antibiotic resistance genes of bacteria. Such studies have revealed that the antibiotic resistance genes are located close to the mobility-associated genes, which promotes their dissemination. An increasing level of information on genomic sequences of resistome should expedite research on drug-resistance in our body and environment, thereby contributing to the development of public health policy. In this review, the high prevalence of antibiotic resistance genes and their exchange in the human and environmental microbiome is discussed with respect to the genomic contents. The relationships among diverse resistomes, related bacterial species, and the antibiotics are reviewed. In addition, recent advances in bioinformatics approaches to investigate such relationships are discussed.201830532649
4088110.9999Expanding the soil antibiotic resistome: exploring environmental diversity. Antibiotic resistance has largely been studied in the context of failure of the drugs in clinical settings. There is now growing evidence that bacteria that live in the environment (e.g. the soil) are multi-drug-resistant. Recent functional screens and the growing accumulation of metagenomic databases are revealing an unexpected density of resistance genes in the environment: the antibiotic resistome. This challenges our current understanding of antibiotic resistance and provides both barriers and opportunities for antimicrobial drug discovery.200717951101
4025120.9999Metagenomic Insights into Transferable Antibiotic Resistance in Oral Bacteria. Antibiotic resistance is considered one of the greatest threats to global public health. Resistance is often conferred by the presence of antibiotic resistance genes (ARGs), which are readily found in the oral microbiome. In-depth genetic analyses of the oral microbiome through metagenomic techniques reveal a broad distribution of ARGs (including novel ARGs) in individuals not recently exposed to antibiotics, including humans in isolated indigenous populations. This has resulted in a paradigm shift from focusing on the carriage of antibiotic resistance in pathogenic bacteria to a broader concept of an oral resistome, which includes all resistance genes in the microbiome. Metagenomics is beginning to demonstrate the role of the oral resistome and horizontal gene transfer within and between commensals in the absence of selective pressure, such as an antibiotic. At the chairside, metagenomic data reinforce our need to adhere to current antibiotic guidelines to minimize the spread of resistance, as such data reveal the extent of ARGs without exposure to antimicrobials and the ecologic changes created in the oral microbiome by even a single dose of antibiotics. The aim of this review is to discuss the role of metagenomics in the investigation of the oral resistome, including the transmission of antibiotic resistance in the oral microbiome. Future perspectives, including clinical implications of the findings from metagenomic investigations of oral ARGs, are also considered.201627183895
4042130.9999Integrons in the intestinal microbiota as reservoirs for transmission of antibiotic resistance genes. The human intestinal microbiota plays a major beneficial role in immune development and resistance to pathogens. The use of antibiotics, however, can cause the spread of antibiotic resistance genes within the resident intestinal microbiota. Important vectors for this are integrons. This review therefore focuses on the integrons in non-pathogenic bacteria as a potential source for the development and persistence of multidrug resistance. Integrons are a group of genetic elements which are assembly platforms that can capture specific gene cassettes and express them. Integrons in pathogenic bacteria have been extensively investigated, while integrons in the intestinal microbiota have not yet gained much attention. Knowledge of the integrons residing in the microbiota, however, can potentially aid in controlling the spread of antibiotic resistance genes to pathogens.201425437798
4052140.9999Functional metagenomics for the investigation of antibiotic resistance. Antibiotic resistance is a major threat to human health and well-being. To effectively combat this problem we need to understand the range of different resistance genes that allow bacteria to resist antibiotics. To do this the whole microbiota needs to be investigated. As most bacteria cannot be cultivated in the laboratory, the reservoir of antibiotic resistance genes in the non-cultivatable majority remains relatively unexplored. Currently the only way to study antibiotic resistance in these organisms is to use metagenomic approaches. Furthermore, the only method that does not require any prior knowledge about the resistance genes is functional metagenomics, which involves expressing genes from metagenomic clones in surrogate hosts. In this review the methods and limitations of functional metagenomics to isolate new antibiotic resistance genes and the mobile genetic elements that mediate their spread are explored.201424556726
4096150.9999Environmental hotspots for antibiotic resistance genes. Bacterial resistance toward broad-spectrum antibiotics has become a major concern in recent years. The threat posed by the infectious bacteria and the pace with which resistance determinants are transmitted needs to be deciphered. Soil and water contain unique and diverse microbial communities as well as pools of naturally occurring antibiotics resistant genes. Overuse of antibiotics along with poor sanitary practices expose these indigenous microbial communities to antibiotic resistance genes from other bacteria and accelerate the process of acquisition and dissemination. Clinical settings, where most antibiotics are prescribed, are hypothesized to serve as a major hotspot. The predisposition of the surrounding environments to a pool of antibiotic-resistant bacteria facilitates rapid antibiotic resistance among the indigenous microbiota in the soil, water, and clinical environments via horizontal gene transfer. This provides favorable conditions for the development of more multidrug-resistant pathogens. Limitations in detecting gene transfer mechanisms have likely left us underestimating the role played by the surrounding environmental hotspots in the emergence of multidrug-resistant bacteria. This review aims to identify the major drivers responsible for the spread of antibiotic resistance and hotspots responsible for the acquisition of antibiotic resistance genes.202134180594
4098160.9999Population Dynamics of Patients with Bacterial Resistance in Hospital Environment. During the past decades, the increase of antibiotic resistance has become a major concern worldwide. The researchers found that superbugs with new type of resistance genes (NDM-1) have two aspects of transmission characteristics; the first is that the antibiotic resistance genes can horizontally transfer among bacteria, and the other is that the superbugs can spread between humans through direct contact. Based on these two transmission mechanisms, we study the dynamics of population in hospital environment where superbugs exist. In this paper, we build three mathematic models to illustrate the dynamics of patients with bacterial resistance in hospital environment. The models are analyzed using stability theory of differential equations. Positive equilibrium points of the system are investigated and their stability analysis is carried out. Moreover, the numerical simulation of the proposed model is also performed which supports the theoretical findings.201626904150
4084170.9999Bacteriophages Contribute to the Spread of Antibiotic Resistance Genes among Foodborne Pathogens of the Enterobacteriaceae Family - A Review. Foodborne illnesses continue to have an economic impact on global health care systems. There is a growing concern regarding the increasing frequency of antibiotic resistance in foodborne bacterial pathogens and how such resistance may affect treatment outcomes. In an effort to better understand how to reduce the spread of resistance, many research studies have been conducted regarding the methods by which antibiotic resistance genes are mobilized and spread between bacteria. Transduction by bacteriophages (phages) is one of many horizontal gene transfer mechanisms, and recent findings have shown phage-mediated transduction to be a significant contributor to dissemination of antibiotic resistance genes. Here, we review the viability of transduction as a contributing factor to the dissemination of antibiotic resistance genes in foodborne pathogens of the Enterobacteriaceae family, including non-typhoidal Salmonella and Shiga toxin-producing Escherichia coli, as well as environmental factors that increase transduction of antibiotic resistance genes.201728676794
4017180.9999Non-antibiotic compounds associated with humans and the environment can promote horizontal transfer of antimicrobial resistance genes. Horizontal gene transfer plays a key role in the global dissemination of antimicrobial resistance (AMR). AMR genes are often carried on self-transmissible plasmids, which are shared amongst bacteria primarily by conjugation. Antibiotic use has been a well-established driver of the emergence and spread of AMR. However, the impact of commonly used non-antibiotic compounds and environmental pollutants on AMR spread has been largely overlooked. Recent studies found common prescription and over-the-counter drugs, artificial sweeteners, food preservatives, and environmental pollutants, can increase the conjugative transfer of AMR plasmids. The potential mechanisms by which these compounds promote plasmid transmission include increased membrane permeability, upregulation of plasmid transfer genes, formation of reactive oxygen species, and SOS response gene induction. Many questions remain around the impact of most non-antibiotic compounds on AMR plasmid conjugation in clinical isolates and the long-term impact on AMR dissemination. By elucidating the role of routinely used pharmaceuticals, food additives, and pollutants in the dissemination of AMR, action can be taken to mitigate their impact by closely monitoring use and disposal. This review will discuss recent progress on understanding the influence of non-antibiotic compounds on plasmid transmission, the mechanisms by which they promote transfer, and the level of risk they pose.202437462915
4034190.9999Environmental and clinical antibiotic resistomes, same only different. The history of antibiotic use in the clinic is one of initial efficacy followed inevitably by the emergence of resistance. Often this resistance is the result of the capture and mobilization of genes that have their origins in environmental reservoirs. Both antibiotic production and resistance are ancient and widely distributed among microbes in the environment. This deep reservoir of resistance offers the opportunity for gene flow into susceptible disease-causing bacteria. Not all resistance genes are equally successfully mobilized, and some dominate in the clinic. The differences and similarities in resistance mechanisms and associated genes among environments reveal a complex interplay between gene capture and mobilization that requires study of gene diversity and gene product function to fully understand the breadth and depth of resistance and the risk to human health.201931330416