Unravelling the mechanisms of antibiotic and heavy metal resistance co-selection in environmental bacteria. - Related Documents




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971501.0000Unravelling the mechanisms of antibiotic and heavy metal resistance co-selection in environmental bacteria. The co-selective pressure of heavy metals is a contributor to the dissemination and persistence of antibiotic resistance genes in environmental reservoirs. The overlapping range of antibiotic and metal contamination and similarities in their resistance mechanisms point to an intertwined evolutionary history. Metal resistance genes are known to be genetically linked to antibiotic resistance genes, with plasmids, transposons, and integrons involved in the assembly and horizontal transfer of the resistance elements. Models of co-selection between metals and antibiotics have been proposed, however, the molecular aspects of these phenomena are in many cases not defined or quantified and the importance of specific metals, environments, bacterial taxa, mobile genetic elements, and other abiotic or biotic conditions are not clear. Co-resistance is often suggested as a dominant mechanism, but interpretations are beset with correlational bias. Proof of principle examples of cross-resistance and co-regulation has been described but more in-depth characterizations are needed, using methodologies that confirm the functional expression of resistance genes and that connect genes with specific bacterial hosts. Here, we comprehensively evaluate the recent evidence for different models of co-selection from pure culture and metagenomic studies in environmental contexts and we highlight outstanding questions.202438897736
969510.9999Antibiotic resistance with particular reference to soil microorganisms. Evidence of increasing resistance to antibiotics in soil and other natural isolates highlights the importance of horizontal transfer of resistance genes in facilitating gene flux in bacteria. Horizontal gene transfer in bacteria is favored by the presence of mobile genetic elements and by the organization of bacterial genomes into operons allowing for the cooperative transfer of genes with related functions. The selective pressure for the spread of resistance genes correlates strongly with the clinical and agricultural overuse of antibiotics. The future of antimicrobial chemotherapy may lie in developing new antimicrobials using information from comparative functional microbial genomics to find genetic targets for antimicrobials and also to understand gene expression enabling selective targeting of genes with expression that correlates with the infectious process.200111446510
971420.9999Antibiotic resistance shaping multi-level population biology of bacteria. Antibiotics have natural functions, mostly involving cell-to-cell signaling networks. The anthropogenic production of antibiotics, and its release in the microbiosphere results in a disturbance of these networks, antibiotic resistance tending to preserve its integrity. The cost of such adaptation is the emergence and dissemination of antibiotic resistance genes, and of all genetic and cellular vehicles in which these genes are located. Selection of the combinations of the different evolutionary units (genes, integrons, transposons, plasmids, cells, communities and microbiomes, hosts) is highly asymmetrical. Each unit of selection is a self-interested entity, exploiting the higher hierarchical unit for its own benefit, but in doing so the higher hierarchical unit might acquire critical traits for its spread because of the exploitation of the lower hierarchical unit. This interactive trade-off shapes the population biology of antibiotic resistance, a composed-complex array of the independent "population biologies." Antibiotics modify the abundance and the interactive field of each of these units. Antibiotics increase the number and evolvability of "clinical" antibiotic resistance genes, but probably also many other genes with different primary functions but with a resistance phenotype present in the environmental resistome. Antibiotics influence the abundance, modularity, and spread of integrons, transposons, and plasmids, mostly acting on structures present before the antibiotic era. Antibiotics enrich particular bacterial lineages and clones and contribute to local clonalization processes. Antibiotics amplify particular genetic exchange communities sharing antibiotic resistance genes and platforms within microbiomes. In particular human or animal hosts, the microbiomic composition might facilitate the interactions between evolutionary units involved in antibiotic resistance. The understanding of antibiotic resistance implies expanding our knowledge on multi-level population biology of bacteria.201323508522
970330.9998Ecology and evolution of antibiotic resistance. The evolution of bacterial pathogens towards antibiotic resistance is not just a relevant problem for human health, but a fascinating example of evolution that can be studied in real time as well. Although most antibiotics are natural compounds produced by environmental microbiota, exposure of bacterial populations to high concentrations of these compounds as the consequence of their introduction for human therapy (and later on for farming) a few decades ago is a very recent situation in evolutionary terms. Resistance genes are originated in environmental bacteria, where they have evolved for millions of years to play different functions that include detoxification, signal trafficking or metabolic functions among others. However, as the consequence of the strong selective pressure exerted by antimicrobials at clinical settings, farms and antibiotic-contaminated natural ecosystems, the selective forces driving the evolution of these potential resistance determinants have changed in the last few decades. Natural ecosystems contain a large number of potential resistance genes; nevertheless, just a few of them are currently present in gene-transfer units and disseminated among pathogens. Along the review, the processes implied in this situation and the consequences for the future evolution of resistance and the environmental microbiota are discussed.200923765924
970240.9998The role of natural environments in the evolution of resistance traits in pathogenic bacteria. Antibiotics are among the most valuable compounds used for fighting human diseases. Unfortunately, pathogenic bacteria have evolved towards resistance. One important and frequently forgotten aspect of antibiotics and their resistance genes is that they evolved in non-clinical (natural) environments before the use of antibiotics by humans. Given that the biosphere is mainly formed by micro-organisms, learning the functional role of antibiotics and their resistance elements in nature has relevant implications both for human health and from an ecological perspective. Recent works have suggested that some antibiotics may serve for signalling purposes at the low concentrations probably found in natural ecosystems, whereas some antibiotic resistance genes were originally selected in their hosts for metabolic purposes or for signal trafficking. However, the high concentrations of antibiotics released in specific habitats (for instance, clinical settings) as a consequence of human activity can shift those functional roles. The pollution of natural ecosystems by antibiotics and resistance genes might have consequences for the evolution of the microbiosphere. Whereas antibiotics produce transient and usually local challenges in microbial communities, antibiotic resistance genes present in gene-transfer units can spread in nature with consequences for human health and the evolution of environmental microbiota that are largely ignored.200919364732
410250.9998Forces 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
969860.9998Potential impact of environmental bacteriophages in spreading antibiotic resistance genes. The idea that bacteriophage transduction plays a role in the horizontal transfer of antibiotic resistance genes is gaining momentum. Such transduction might be vital in horizontal transfer from environmental to human body-associated biomes and here we review many lines of evidence supporting this notion. It is well accepted that bacteriophages are the most abundant entities in most environments, where they have been shown to be quite persistent. This fact, together with the ability of many phages to infect bacteria belonging to different taxa, makes them suitable vehicles for gene transfer. Metagenomic studies confirm that substantial percentages of the bacteriophage particles present in most environments contain bacterial genes, including mobile genetic elements and antibiotic resistance genes. When specific genes of resistance to antibiotics are detected by real-time PCR in the bacteriophage populations of different environments, only tenfold lower numbers of these genes are observed, compared with those found in the corresponding bacterial populations. In addition, the antibiotic resistance genes from these bacteriophages are functional and generate resistance to the bacteria when these genes are transfected. Finally, reports about the transduction of antibiotic resistance genes are on the increase.201323701331
969470.9998Antibiotics as selectors and accelerators of diversity in the mechanisms of resistance: from the resistome to genetic plasticity in the β-lactamases world. Antibiotics and antibiotic resistance determinants, natural molecules closely related to bacterial physiology and consistent with an ancient origin, are not only present in antibiotic-producing bacteria. Throughput sequencing technologies have revealed an unexpected reservoir of antibiotic resistance in the environment. These data suggest that co-evolution between antibiotic and antibiotic resistance genes has occurred since the beginning of time. This evolutionary race has probably been slow because of highly regulated processes and low antibiotic concentrations. Therefore to understand this global problem, a new variable must be introduced, that the antibiotic resistance is a natural event, inherent to life. However, the industrial production of natural and synthetic antibiotics has dramatically accelerated this race, selecting some of the many resistance genes present in nature and contributing to their diversification. One of the best models available to understand the biological impact of selection and diversification are β-lactamases. They constitute the most widespread mechanism of resistance, at least among pathogenic bacteria, with more than 1000 enzymes identified in the literature. In the last years, there has been growing concern about the description, spread, and diversification of β-lactamases with carbapenemase activity and AmpC-type in plasmids. Phylogenies of these enzymes help the understanding of the evolutionary forces driving their selection. Moreover, understanding the adaptive potential of β-lactamases contribute to exploration the evolutionary antagonists trajectories through the design of more efficient synthetic molecules. In this review, we attempt to analyze the antibiotic resistance problem from intrinsic and environmental resistomes to the adaptive potential of resistance genes and the driving forces involved in their diversification, in order to provide a global perspective of the resistance problem.201323404545
969980.9998Bottlenecks in the transferability of antibiotic resistance from natural ecosystems to human bacterial pathogens. It is generally accepted that resistance genes acquired by human pathogens through horizontal gene transfer originated in environmental, non-pathogenic bacteria. As a consequence, there is increasing concern on the roles that natural, non-clinical ecosystems, may play in the evolution of resistance. Recent studies have shown that the variability of determinants that can provide antibiotic resistance on their expression in a heterologous host is much larger than what is actually found in human pathogens, which implies the existence of bottlenecks modulating the transfer, spread, and stability of antibiotic resistance genes. In this review, the role that different factors such as founder effects, ecological connectivity, fitness costs, or second-order selection may have on the establishment of a specific resistance determinant in a population of bacterial pathogens is analyzed.201122319513
401090.9998Integrons in the Age of Antibiotic Resistance: Evolution, Mechanisms, and Environmental Implications: A Review. Integrons, which are genetic components commonly found in bacteria, possess the remarkable capacity to capture gene cassettes, incorporate them into their structure, and thereby contribute to an increase in genomic complexity and phenotypic diversity. This adaptive mechanism allows integrons to play a significant role in acquiring, expressing, and spreading antibiotic resistance genes in the modern age. To assess the current challenges posed by integrons, it is necessary to have a thorough understanding of their characteristics. This review aims to elucidate the structure and evolutionary history of integrons, highlighting how the use of antibiotics has led to the preferential selection of integrons in various environments. Additionally, it explores their current involvement in antibiotic resistance and their dissemination across diverse settings, while considering potential transmission factors and routes. This review delves into the arrangement of gene cassettes within integrons, their ability to rearrange, the mechanisms governing their expression, and the process of excision. Furthermore, this study examines the presence of clinically relevant integrons in a wide range of environmental sources, shedding light on how anthropogenic influences contribute to their propagation into the environment.202439770781
4034100.9998Environmental 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
4170110.9998The Spread of Antibiotic Resistance Is Driven by Plasmids Among the Fastest Evolving and of Broadest Host Range. Microorganisms endure novel challenges for which other microorganisms in other biomes may have already evolved solutions. This is the case of nosocomial bacteria under antibiotic therapy because antibiotics are of ancient natural origin and resistances to them have previously emerged in environmental bacteria. In such cases, the rate of adaptation crucially depends on the acquisition of genes by horizontal transfer of plasmids from distantly related bacteria in different biomes. We hypothesized that such processes should be driven by plasmids among the most mobile and evolvable. We confirmed these predictions by showing that plasmid species encoding antibiotic resistance are very mobile, have broad host ranges, while showing higher rates of homologous recombination and faster turnover of gene repertoires than the other plasmids. These characteristics remain outstanding when we remove resistance plasmids from our dataset, suggesting that antibiotic resistance genes are preferentially acquired and carried by plasmid species that are intrinsically very mobile and plastic. Evolvability and mobility facilitate the transfer of antibiotic resistance, and presumably of other phenotypes, across distant taxonomic groups and biomes. Hence, plasmid species, and possibly those of other mobile genetic elements, have differentiated and predictable roles in the spread of novel traits.202540098486
9651120.9998Host- plasmid network structure in wastewater is linked to antimicrobial resistance genes. As mobile genetic elements, plasmids are central for our understanding of antimicrobial resistance spread in microbial communities. Plasmids can have varying fitness effects on their host bacteria, which will markedly impact their role as antimicrobial resistance vectors. Using a plasmid population model, we first show that beneficial plasmids interact with a higher number of hosts than costly plasmids when embedded in a community with multiple hosts and plasmids. We then analyse the network of a natural host-plasmid wastewater community from a Hi-C metagenomics dataset. As predicted by the model, we find that antimicrobial resistance encoding plasmids, which are likely to have positive fitness effects on their hosts in wastewater, interact with more bacterial taxa than non-antimicrobial resistance plasmids and are disproportionally important for connecting the entire network compared to non- antimicrobial resistance plasmids. This highlights the role of antimicrobials in restructuring host-plasmid networks by increasing the benefits of antimicrobial resistance carrying plasmids, which can have consequences for the spread of antimicrobial resistance genes through microbial networks. Furthermore, that antimicrobial resistance encoding plasmids are associated with a broader range of hosts implies that they will be more robust to turnover of bacterial strains.202438228585
9838130.9998Interactions between plasmids and other mobile genetic elements affect their transmission and persistence. Plasmids are genetic elements that play a role in bacterial evolution by providing new genes that promote adaptation to diverse conditions. Plasmids are also known to reduce bacterial competitiveness in the absence of selection for plasmid-encoded traits. It is easier to understand plasmid persistence when considering the evidence that plasmid maintenance can improve during co-evolution with the bacterial host, i.e. the chromosome. However, bacteria isolated from nature often harbor diverse mobile elements: phages, transposons, genomic islands and even other plasmids. Recent interest has emerged on the role such elements play on the persistence and evolution of plasmids. Here, we mainly review interactions between different plasmids, but also discuss their interactions with other genetic elements. We focus on interactions that impact fundamental plasmid traits, such as the fitness effect imposed on their hosts and the transfer efficiency into new host cells. We illustrate these phenomena with examples concerning clinically relevant organisms and the spread of plasmids carrying antibiotic resistance genes and virulence factors.201930771401
9701140.9998Environmental factors influencing the development and spread of antibiotic resistance. Antibiotic resistance and its wider implications present us with a growing healthcare crisis. Recent research points to the environment as an important component for the transmission of resistant bacteria and in the emergence of resistant pathogens. However, a deeper understanding of the evolutionary and ecological processes that lead to clinical appearance of resistance genes is still lacking, as is knowledge of environmental dispersal barriers. This calls for better models of how resistance genes evolve, are mobilized, transferred and disseminated in the environment. Here, we attempt to define the ecological and evolutionary environmental factors that contribute to resistance development and transmission. Although mobilization of resistance genes likely occurs continuously, the great majority of such genetic events do not lead to the establishment of novel resistance factors in bacterial populations, unless there is a selection pressure for maintaining them or their fitness costs are negligible. To enable preventative measures it is therefore critical to investigate under what conditions and to what extent environmental selection for resistance takes place. In addition, understanding dispersal barriers is not only key to evaluate risks, but also to prevent resistant pathogens, as well as novel resistance genes, from reaching humans.201829069382
4283150.9998Development, spread and persistence of antibiotic resistance genes (ARGs) in the soil microbiomes through co-selection. Bacterial pathogens resistant to multiple antibiotics are emergent threat to the public health which may evolve in the environment due to the co-selection of antibiotic resistance, driven by poly aromatic hydrocarbons (PAHs) and/or heavy metal contaminations. The co-selection of antibiotic resistance (AMR) evolves through the co-resistance or cross-resistance, or co-regulatory mechanisms, present in bacteria. The persistent toxic contaminants impose widespread pressure in both clinical and environmental setting, and may potentially cause the maintenance and spread of antibiotic resistance genes (ARGs). In the past few years, due to exponential increase of AMR, numerous drugs are now no longer effective to treat infectious diseases, especially in cases of bacterial infections. In this mini-review, we have described the role of co-resistance and cross-resistance as main sources for co-selection of ARGs; while other co-regulatory mechanisms are also involved with cross-resistance that regulates multiple ARGs. However, co-factors also support selections, which results in development and evolution of ARGs in absence of antibiotic pressure. Efflux pumps present on the same mobile genetic elements, possibly due to the function of Class 1 integrons (Int1), may increase the presence of ARGs into the environment, which further is promptly changed as per environmental conditions. This review also signifies that mutation plays important role in the expansion of ARGs due to presence of diverse types of anthropogenic pollutants, which results in overexpression of efflux pump with higher bacterial fitness cost; and these situations result in acquisition of resistant genes. The future aspects of co-selection with involvement of systems biology, synthetic biology and gene network approaches have also been discussed.202032681784
4033160.9998Evolution and ecology of antibiotic resistance genes. A new perspective on the topic of antibiotic resistance is beginning to emerge based on a broader evolutionary and ecological understanding rather than from the traditional boundaries of clinical research of antibiotic-resistant bacterial pathogens. Phylogenetic insights into the evolution and diversity of several antibiotic resistance genes suggest that at least some of these genes have a long evolutionary history of diversification that began well before the 'antibiotic era'. Besides, there is no indication that lateral gene transfer from antibiotic-producing bacteria has played any significant role in shaping the pool of antibiotic resistance genes in clinically relevant and commensal bacteria. Most likely, the primary antibiotic resistance gene pool originated and diversified within the environmental bacterial communities, from which the genes were mobilized and penetrated into taxonomically and ecologically distant bacterial populations, including pathogens. Dissemination and penetration of antibiotic resistance genes from antibiotic producers were less significant and essentially limited to other high G+C bacteria. Besides direct selection by antibiotics, there is a number of other factors that may contribute to dissemination and maintenance of antibiotic resistance genes in bacterial populations.200717490428
9667170.9998Novel resistance functions uncovered using functional metagenomic investigations of resistance reservoirs. Rates of infection with antibiotic-resistant bacteria have increased precipitously over the past several decades, with far-reaching healthcare and societal costs. Recent evidence has established a link between antibiotic resistance genes in human pathogens and those found in non-pathogenic, commensal, and environmental organisms, prompting deeper investigation of natural and human-associated reservoirs of antibiotic resistance. Functional metagenomic selections, in which shotgun-cloned DNA fragments are selected for their ability to confer survival to an indicator host, have been increasingly applied to the characterization of many antibiotic resistance reservoirs. These experiments have demonstrated that antibiotic resistance genes are highly diverse and widely distributed, many times bearing little to no similarity to known sequences. Through unbiased selections for survival to antibiotic exposure, functional metagenomics can improve annotations by reducing the discovery of false-positive resistance and by allowing for the identification of previously unrecognizable resistance genes. In this review, we summarize the novel resistance functions uncovered using functional metagenomic investigations of natural and human-impacted resistance reservoirs. Examples of novel antibiotic resistance genes include those highly divergent from known sequences, those for which sequence is entirely unable to predict resistance function, bifunctional resistance genes, and those with unconventional, atypical resistance mechanisms. Overcoming antibiotic resistance in the clinic will require a better understanding of existing resistance reservoirs and the dissemination networks that govern horizontal gene exchange, informing best practices to limit the spread of resistance-conferring genes to human pathogens.201323760651
9841180.9998Genetic dominance governs the evolution and spread of mobile genetic elements in bacteria. Mobile genetic elements (MGEs), such as plasmids, promote bacterial evolution through horizontal gene transfer (HGT). However, the rules governing the repertoire of traits encoded on MGEs remain unclear. In this study, we uncovered the central role of genetic dominance shaping genetic cargo in MGEs, using antibiotic resistance as a model system. MGEs are typically present in more than one copy per host bacterium, and as a consequence, genetic dominance favors the fixation of dominant mutations over recessive ones. In addition, genetic dominance also determines the phenotypic effects of horizontally acquired MGE-encoded genes, silencing recessive alleles if the recipient bacterium already carries a wild-type copy of the gene. The combination of these two effects governs the catalog of genes encoded on MGEs. Our results help to understand how MGEs evolve and spread, uncovering the neglected influence of genetic dominance on bacterial evolution. Moreover, our findings offer a framework to forecast the spread and evolvability of MGE-encoded genes, which encode traits of key human interest, such as virulence or antibiotic resistance.202032571917
3783190.9998Ecology drives a global network of gene exchange connecting the human microbiome. Horizontal gene transfer (HGT), the acquisition of genetic material from non-parental lineages, is known to be important in bacterial evolution. In particular, HGT provides rapid access to genetic innovations, allowing traits such as virulence, antibiotic resistance and xenobiotic metabolism to spread through the human microbiome. Recent anecdotal studies providing snapshots of active gene flow on the human body have highlighted the need to determine the frequency of such recent transfers and the forces that govern these events. Here we report the discovery and characterization of a vast, human-associated network of gene exchange, large enough to directly compare the principal forces shaping HGT. We show that this network of 10,770 unique, recently transferred (more than 99% nucleotide identity) genes found in 2,235 full bacterial genomes, is shaped principally by ecology rather than geography or phylogeny, with most gene exchange occurring between isolates from ecologically similar, but geographically separated, environments. For example, we observe 25-fold more HGT between human-associated bacteria than among ecologically diverse non-human isolates (P = 3.0 × 10(-270)). We show that within the human microbiome this ecological architecture continues across multiple spatial scales, functional classes and ecological niches with transfer further enriched among bacteria that inhabit the same body site, have the same oxygen tolerance or have the same ability to cause disease. This structure offers a window into the molecular traits that define ecological niches, insight that we use to uncover sources of antibiotic resistance and identify genes associated with the pathology of meningitis and other diseases.201122037308