Novel Insights into Selection for Antibiotic Resistance in Complex Microbial Communities. - Related Documents




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963001.0000Novel Insights into Selection for Antibiotic Resistance in Complex Microbial Communities. Recent research has demonstrated that selection for antibiotic resistance occurs at very low antibiotic concentrations in single-species experiments, but the relevance of these findings when species are embedded in complex microbial communities is unclear. We show that the strength of selection for naturally occurring resistance alleles in a complex community remains constant from low subinhibitory to above clinically relevant concentrations. Selection increases with antibiotic concentration before reaching a plateau where selection remains constant over a 2-order-magnitude concentration range. This is likely to be due to cross protection of the susceptible bacteria in the community following rapid extracellular antibiotic degradation by the resistant population, shown experimentally through a combination of chemical quantification and bacterial growth experiments. Metagenome and 16S rRNA analyses of sewage-derived bacterial communities evolved under cefotaxime exposure show preferential enrichment for bla(CTX-M) genes over all other beta-lactamase genes, as well as positive selection and co-selection for antibiotic resistant, opportunistic pathogens. These findings have far-reaching implications for our understanding of the evolution of antibiotic resistance, by challenging the long-standing assumption that selection occurs in a dose-dependent manner.IMPORTANCE Antibiotic resistance is one of the greatest global issues facing society. Still, comparatively little is known about selection for resistance at very low antibiotic concentrations. We show that the strength of selection for clinically important resistance genes within a complex bacterial community can remain constant across a large antibiotic concentration range (wide selective space). Therefore, largely understudied ecological compartments could be just as important as clinical environments for selection of antibiotic resistance.201830042197
962910.9999Costs of antibiotic resistance genes depend on host strain and environment and can influence community composition. Antibiotic resistance genes (ARGs) benefit host bacteria in environments containing corresponding antibiotics, but it is less clear how they are maintained in environments where antibiotic selection is weak or sporadic. In particular, few studies have measured if the direct effect of ARGs on host fitness is fixed or if it depends on the host strain, perhaps marking some ARG-host combinations as selective refuges that can maintain ARGs in the absence of antibiotic selection. We quantified the fitness effects of six ARGs in 11 diverse Escherichia spp. strains. Three ARGs (bla(TEM-116), cat and dfrA5, encoding resistance to β-lactams, chloramphenicol, and trimethoprim, respectively) imposed an overall cost, but all ARGs had an effect in at least one host strain, reflecting a significant strain interaction effect. A simulation predicts these interactions can cause the success of ARGs to depend on available host strains, and, to a lesser extent, can cause host strain success to depend on the ARGs present in a community. These results indicate the importance of considering ARG effects across different host strains, and especially the potential of refuge strains to allow resistance to persist in the absence of direct selection, in efforts to understand resistance dynamics.202438889784
399420.9999Environmental Biofilms as Reservoirs for Antimicrobial Resistance. Characterizing the response of microbial communities to a range of antibiotic concentrations is one of the strategies used to understand the impact of antibiotic resistance. Many studies have described the occurrence and prevalence of antibiotic resistance in microbial communities from reservoirs such as hospitals, sewage, and farm feedlots, where bacteria are often exposed to high and/or constant concentrations of antibiotics. Outside of these sources, antibiotics generally occur at lower, sub-minimum inhibitory concentrations (sub-MICs). The constant exposure to low concentrations of antibiotics may serve as a chemical "cue" that drives development of antibiotic resistance. Low concentrations of antibiotics have not yet been broadly described in reservoirs outside of the aforementioned environments, nor is the transfer and dissemination of antibiotic resistant bacteria and genes within natural microbial communities fully understood. This review will thus focus on low antibiotic-concentration environmental reservoirs and mechanisms that are important in the dissemination of antibiotic resistance to help identify key knowledge gaps concerning the environmental resistome.202134970233
410230.9999Forces 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
399340.9999Environmental dissemination of antibiotic resistance genes and correlation to anthropogenic contamination with antibiotics. Antibiotic resistance is a growing problem which threatens modern healthcare globally. Resistance has traditionally been viewed as a clinical problem, but recently non-clinical environments have been highlighted as an important factor in the dissemination of antibiotic resistance genes (ARGs). Horizontal gene transfer (HGT) events are likely to be common in aquatic environments; integrons in particular are well suited for mediating environmental dissemination of ARGs. A growing body of evidence suggests that ARGs are ubiquitous in natural environments. Particularly, elevated levels of ARGs and integrons in aquatic environments are correlated to proximity to anthropogenic activities. The source of this increase is likely to be routine discharge of antibiotics and resistance genes, for example, via wastewater or run-off from livestock facilities and agriculture. While very high levels of antibiotic contamination are likely to select for resistant bacteria directly, the role of sub-inhibitory concentrations of antibiotics in environmental antibiotic resistance dissemination remains unclear. In vitro studies have shown that low levels of antibiotics can select for resistant mutants and also facilitate HGT, indicating the need for caution. Overall, it is becoming increasingly clear that the environment plays an important role in dissemination of antibiotic resistance; further studies are needed to elucidate key aspects of this process. Importantly, the levels of environmental antibiotic contamination at which resistant bacteria are selected for and HGT is facilitated at should be determined. This would enable better risk analyses and facilitate measures for preventing dissemination and development of antibiotic resistance in the environment.201526356096
403650.9999Man-made microbial resistances in built environments. Antimicrobial resistance is a serious threat to global public health, but little is known about the effects of microbial control on the microbiota and its associated resistome. Here we compare the microbiota present on surfaces of clinical settings with other built environments. Using state-of-the-art metagenomics approaches and genome and plasmid reconstruction, we show that increased confinement and cleaning is associated with a loss of microbial diversity and a shift from Gram-positive bacteria, such as Actinobacteria and Firmicutes, to Gram-negative such as Proteobacteria. Moreover, the microbiome of highly maintained built environments has a different resistome when compared to other built environments, as well as a higher diversity in resistance genes. Our results highlight that the loss of microbial diversity correlates with an increase in resistance, and the need for implementing strategies to restore bacterial diversity in certain built environments.201930814504
399760.9999Pyrosequencing of antibiotic-contaminated river sediments reveals high levels of resistance and gene transfer elements. The high and sometimes inappropriate use of antibiotics has accelerated the development of antibiotic resistance, creating a major challenge for the sustainable treatment of infections world-wide. Bacterial communities often respond to antibiotic selection pressure by acquiring resistance genes, i.e. mobile genetic elements that can be shared horizontally between species. Environmental microbial communities maintain diverse collections of resistance genes, which can be mobilized into pathogenic bacteria. Recently, exceptional environmental releases of antibiotics have been documented, but the effects on the promotion of resistance genes and the potential for horizontal gene transfer have yet received limited attention. In this study, we have used culture-independent shotgun metagenomics to investigate microbial communities in river sediments exposed to waste water from the production of antibiotics in India. Our analysis identified very high levels of several classes of resistance genes as well as elements for horizontal gene transfer, including integrons, transposons and plasmids. In addition, two abundant previously uncharacterized resistance plasmids were identified. The results suggest that antibiotic contamination plays a role in the promotion of resistance genes and their mobilization from environmental microbes to other species and eventually to human pathogens. The entire life-cycle of antibiotic substances, both before, under and after usage, should therefore be considered to fully evaluate their role in the promotion of resistance.201121359229
428470.9999Overview on the role of heavy metals tolerance on developing antibiotic resistance in both Gram-negative and Gram-positive bacteria. Environmental health is a critical concern, continuously contaminated by physical and biological components (viz., anthropogenic activity), which adversely affect on biodiversity, ecosystems and human health. Nonetheless, environmental pollution has great impact on microbial communities, especially bacteria, which try to evolve in changing environment. For instance, during the course of adaptation, bacteria easily become resistance to antibiotics and heavy metals. Antibiotic resistance genes are now one of the most vital pollutants, provided as a source of frequent horizontal gene transfer. In this review, the environmental cause of multidrug resistance (MDR) that was supposed to be driven by either heavy metals or combination of environmental factors was essentially reviewed, especially focussed on the correlation between accumulation of heavy metals and development of MDR by bacteria. This kind of correlation was seemed to be non-significant, i.e. paradoxical. Gram-positive bacteria accumulating much of toxic heavy metal (i.e. highly stress tolerance) were unlikely to become MDR, whereas Gram-negative bacteria that often avoid accumulation of toxic heavy metal by efflux pump systems were come out to be more prone to MDR. So far, other than antibiotic contaminant, no such available data strongly support the direct influence of heavy metals in bacterial evolution of MDR; combinations of factors may drive the evolution of antibiotic resistance. Therefore, Gram-positive bacteria are most likely to be an efficient member in treatment of industrial waste water, especially in the removal of heavy metals, perhaps inducing the less chance of antibiotic resistance pollution in the environment.202133811263
382680.9999Co-resistance: an opportunity for the bacteria and resistance genes. Co-resistance involves transfer of several genes into the same bacteria and/or the acquisition of mutations in different genetic loci affecting different antimicrobials whereas pleiotropic resistance implies the same genetic event affecting several antimicrobials. There is an increasing prevalence of isolates with co-resistance which are over-represented within the so-called high-risk clones. Compensatory events avoid fitness cost of co-resistance, even in the absence of antimicrobials. Nevertheless, they might be selected by different antimicrobials and a single agent might select co-resistant isolates. This process, named as co-selection, is not avoided with cycling or mixing strategies of antimicrobial use. Co-resistance and co-selection processes increase the opportunity for persistence of the bacteria and resistance genes and should be considered when designing strategies for decreasing antimicrobial resistance.201121840259
647990.9999Fate and transport of antibiotic residues and antibiotic resistance genes following land application of manure waste. Antibiotics are used in animal livestock production for therapeutic treatment of disease and at subtherapeutic levels for growth promotion and improvement of feed efficiency. It is estimated that approximately 75% of antibiotics are not absorbed by animals and are excreted in waste. Antibiotic resistance selection occurs among gastrointestinal bacteria, which are also excreted in manure and stored in waste holding systems. Land application of animal waste is a common disposal method used in the United States and is a means for environmental entry of both antibiotics and genetic resistance determinants. Concerns for bacterial resistance gene selection and dissemination of resistance genes have prompted interest about the concentrations and biological activity of drug residues and break-down metabolites, and their fate and transport. Fecal bacteria can survive for weeks to months in the environment, depending on species and temperature, however, genetic elements can persist regardless of cell viability. Phylogenetic analyses indicate antibiotic resistance genes have evolved, although some genes have been maintained in bacteria before the modern antibiotic era. Quantitative measurements of drug residues and levels of resistance genes are needed, in addition to understanding the environmental mechanisms of genetic selection, gene acquisition, and the spatiotemporal dynamics of these resistance genes and their bacterial hosts. This review article discusses an accumulation of findings that address aspects of the fate, transport, and persistence of antibiotics and antibiotic resistance genes in natural environments, with emphasis on mechanisms pertaining to soil environments following land application of animal waste effluent.200919398507
4101100.9999What 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
9700110.9999Predation and selection for antibiotic resistance in natural environments. Genes encoding resistance to antibiotics appear, like the antibiotics themselves, to be ancient, originating long before the rise of the era of anthropogenic antibiotics. However, detailed understanding of the specific biological advantages of antibiotic resistance in natural environments is still lacking, thus limiting our efforts to prevent environmental influx of resistance genes. Here, we propose that antibiotic-resistant cells not only evade predation from antibiotic producers but also take advantage of nutrients released from cells that are killed by the antibiotic-producing bacteria. Thus, predation is potentially an important mechanism for driving antibiotic resistance during slow or stationary phase of growth when nutrients are deprived. This adds to explain the ancient nature and widespread occurrence of antibiotic resistance in natural environments unaffected by anthropogenic antibiotics. In particular, we suggest that nutrient-poor environments including indoor environments, for example, clean rooms and intensive care units may serve as a reservoir and source for antibiotic-producing as well as antibiotic-resistant bacteria.201626989434
4033120.9999Evolution 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
9657130.9999Machine Learning Leveraging Genomes from Metagenomes Identifies Influential Antibiotic Resistance Genes in the Infant Gut Microbiome. Antibiotic resistance in pathogens is extensively studied, and yet little is known about how antibiotic resistance genes of typical gut bacteria influence microbiome dynamics. Here, we leveraged genomes from metagenomes to investigate how genes of the premature infant gut resistome correspond to the ability of bacteria to survive under certain environmental and clinical conditions. We found that formula feeding impacts the resistome. Random forest models corroborated by statistical tests revealed that the gut resistome of formula-fed infants is enriched in class D beta-lactamase genes. Interestingly, Clostridium difficile strains harboring this gene are at higher abundance in formula-fed infants than C. difficile strains lacking this gene. Organisms with genes for major facilitator superfamily drug efflux pumps have higher replication rates under all conditions, even in the absence of antibiotic therapy. Using a machine learning approach, we identified genes that are predictive of an organism's direction of change in relative abundance after administration of vancomycin and cephalosporin antibiotics. The most accurate results were obtained by reducing annotated genomic data to five principal components classified by boosted decision trees. Among the genes involved in predicting whether an organism increased in relative abundance after treatment are those that encode subclass B2 beta-lactamases and transcriptional regulators of vancomycin resistance. This demonstrates that machine learning applied to genome-resolved metagenomics data can identify key genes for survival after antibiotics treatment and predict how organisms in the gut microbiome will respond to antibiotic administration. IMPORTANCE The process of reconstructing genomes from environmental sequence data (genome-resolved metagenomics) allows unique insight into microbial systems. We apply this technique to investigate how the antibiotic resistance genes of bacteria affect their ability to flourish in the gut under various conditions. Our analysis reveals that strain-level selection in formula-fed infants drives enrichment of beta-lactamase genes in the gut resistome. Using genomes from metagenomes, we built a machine learning model to predict how organisms in the gut microbial community respond to perturbation by antibiotics. This may eventually have clinical applications.201829359195
4127140.9999The Perfect Condition for the Rising of Superbugs: Person-to-Person Contact and Antibiotic Use Are the Key Factors Responsible for the Positive Correlation between Antibiotic Resistance Gene Diversity and Virulence Gene Diversity in Human Metagenomes. Human metagenomes with a high diversity of virulence genes tend to have a high diversity of antibiotic-resistance genes and vice-versa. To understand this positive correlation, we simulated the transfer of these genes and bacterial pathogens in a community of interacting people that take antibiotics when infected by pathogens. Simulations show that people with higher diversity of virulence and resistance genes took antibiotics long ago, not recently. On the other extreme, we find people with low diversity of both gene types because they took antibiotics recently-while antibiotics select specific resistance genes, they also decrease gene diversity by eliminating bacteria. In general, the diversity of virulence and resistance genes becomes positively correlated whenever the transmission probability between people is higher than the probability of losing resistance genes. The positive correlation holds even under changes of several variables, such as the relative or total diversity of virulence and resistance genes, the contamination probability between individuals, the loss rate of resistance genes, or the social network type. Because the loss rate of resistance genes may be shallow, we conclude that the transmission between people and antibiotic usage are the leading causes for the positive correlation between virulence and antibiotic-resistance genes.202134065307
9686150.9999Selective pressures for public antibiotic resistance. The rapid increase of antibiotic-resistant pathogens is severely limiting our current treatment possibilities. An important subset of the resistance mechanisms conferring antibiotic resistance have public effects, allowing otherwise susceptible bacteria to also survive antibiotic treatment. As susceptible bacteria can survive treatment without bearing the metabolic cost of producing the resistance mechanism, there is potential to increase their relative frequency in the population and, as such, select against resistant bacteria. Multiple studies showed that this altered selection for resistance is dependent on various environmental and treatment parameters. In this review, we provide a comprehensive overview of their most important findings and describe the main factors impacting the selection for resistance. In-depth understanding of the driving forces behind selection can aid in the design and implementation of alternative treatments which limit the risk of resistance development.202539158370
3979160.9999Mathematical modelling of antimicrobial resistance in agricultural waste highlights importance of gene transfer rate. Antimicrobial resistance is of global concern. Most antimicrobial use is in agriculture; manures and slurry are especially important because they contain a mix of bacteria, including potential pathogens, antimicrobial resistance genes and antimicrobials. In many countries, manures and slurry are stored, especially over winter, before spreading onto fields as organic fertilizer. Thus, these are a potential location for gene exchange and selection for resistance. We develop and analyse a mathematical model to quantify the spread of antimicrobial resistance in stored agricultural waste. We use parameters from a slurry tank on a UK dairy farm as an exemplar. We show that the spread of resistance depends in a subtle way on the rates of gene transfer and antibiotic inflow. If the gene transfer rate is high, then its reduction controls resistance, while cutting antibiotic inflow has little impact. If the gene transfer rate is low, then reducing antibiotic inflow controls resistance. Reducing length of storage can also control spread of resistance. Bacterial growth rate, fitness costs of carrying antimicrobial resistance and proportion of resistant bacteria in animal faeces have little impact on spread of resistance. Therefore, effective treatment strategies depend critically on knowledge of gene transfer rates.201626906100
4283170.9998Development, 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
7705180.9998Oxytetracycline reduces the diversity of tetracycline-resistance genes in the Galleria mellonella gut microbiome. BACKGROUND: Clinically-relevant multidrug resistance is sometimes present in bacteria not exposed to human-made antibiotics, in environments without extreme selective pressures, such as the insect gut. The use of antibiotics on naïve microbiomes often leads to decreased microbe diversity and increased antibiotic resistance. RESULTS: Here we investigate the impact of antibiotics on the insect gut microbiome by identifying tetracycline-resistance genes in the gut bacteria of greater wax moth (Galleria mellonella) larvae, feeding on artificial food containing oxytetracycline. We determined that G. mellonella can be raised on artificial food for over five generations and that the insects tolerate low doses of antibiotics in their diets, but doses of oxytetracycline higher than sub-inhibitory lead to early larval mortality. In our experiments, greater wax moth larvae had a sparse microbiome, which is consistent with previous findings. Additionally, we determined that the microbiome of G. mellonella larvae not exposed to antibiotics carries a number of tetracycline-resistance genes and some of that diversity is lost upon exposure to strong selective pressure. CONCLUSIONS: We show that G. mellonella larvae can be raised on artificial food, including antibiotics, for several generations and that the microbiome can be sampled. We show that, in the absence of antibiotics, the insect gut microbiome can maintain a diverse pool of tetracycline-resistance genes. Selective pressure, from exposure to the antibiotic oxytetracycline, leads to microbiome changes and alteration in the tetracycline-resistance gene pool.201830594143
9003190.9998Extreme Environments and High-Level Bacterial Tellurite Resistance. Bacteria have long been known to possess resistance to the highly toxic oxyanion tellurite, most commonly though reduction to elemental tellurium. However, the majority of research has focused on the impact of this compound on microbes, namely E. coli, which have a very low level of resistance. Very little has been done regarding bacteria on the other end of the spectrum, with three to four orders of magnitude greater resistance than E. coli. With more focus on ecologically-friendly methods of pollutant removal, the use of bacteria for tellurite remediation, and possibly recovery, further highlights the importance of better understanding the effect on microbes, and approaches for resistance/reduction. The goal of this review is to compile current research on bacterial tellurite resistance, with a focus on high-level resistance by bacteria inhabiting extreme environments.201931766694