# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 474 | 0 | 0.9981 | Novel antibiotic resistance profiles in bacteria isolated from oil fly larvae Helaeomyia petrolei living in the La Brea Tar Pits. Larvae from the petroleum oil fly, Helaeomyia petrolei, live in the asphaltene and polyaromatic hydrocarbon rich asphalt seeps of Rancho La Brea, Los Angeles, California. These larvae pass high amounts of viscous asphalt through their digestive system, and their gut microbiota is exposed to these extreme conditions. Environmental stress response mechanisms can co-select for antibiotic resistance, and in the current study we used 16S rRNA and genomic sequencing along with the Comprehensive Antibiotic Resistance Database (CARD) tools to characterize antibiotic resistance profiles from six bacteria previously isolated from the oil fly larval intestinal tract, linking phenotypic and genotypic resistance profiles. The isolates contain a core set of antibiotic resistance determinants along with determinants that are rarely found in these species. Comparing these oil fly isolates to the phenotypic prevalence data generated by the CARD Resistance Gene Identifier revealed sixteen instances where the oil fly bacteria appeared to carry a resistance not seen in related taxa in the database, suggesting a novel suite of resistance families in the oil fly isolates compared to other members of the same taxa. Results highlight the functional duality of genes that simultaneously code for antibiotic resistance and survival under extreme conditions, and expand our understanding of the ecological and evolutionary role of antibiotic resistance genes in environmental habitats. | 2024 | 39718641 |
| 7692 | 1 | 0.9981 | 16S rRNA gene sequencing data of the human skin microbiome before and after swimming in the ocean. These data represent the abundance, diversity and predicted function gene profiles of the microbial communities present on human skin before and after swimming in the ocean. The skin microbiome has been shown to provide protection against infection from pathogenic bacteria. It is well-known that exposure to ocean water can cause skin infection, but little is known about how exposure can alter the bacterial communities on the skin. Skin microbiome samples were collected from human participants before and after swimming in the ocean. These data were used to analyze the changes in abundance and diversity of microbial communities on the skin and the changes in the functional profiles of the bacteria, specifically focusing on genes involved in antibiotic resistance and bacterial virulence. | 2021 | 34189199 |
| 8413 | 2 | 0.9980 | Investigating mechanisms underlying genetic resistance to Salmon Rickettsial Syndrome in Atlantic salmon using RNA sequencing. BACKGROUND: Salmon Rickettsial Syndrome (SRS), caused by Piscirickettsia salmonis, is one of the primary causes of morbidity and mortality in Atlantic salmon aquaculture, particularly in Chile. Host resistance is a heritable trait, and functional genomic studies have highlighted genes and pathways important in the response of salmon to the bacteria. However, the functional mechanisms underpinning genetic resistance are not yet well understood. In the current study, a large population of salmon pre-smolts were challenged with P. salmonis, with mortality levels recorded and samples taken for genotyping. In parallel, head kidney and liver samples were taken from animals of the same population with high and low genomic breeding values for resistance, and used for RNA-Sequencing to compare their transcriptome profile both pre and post infection. RESULTS: A significant and moderate heritability (h(2) = 0.43) was shown for the trait of binary survival. Genome-wide association analyses using 38 K imputed SNP genotypes across 2265 animals highlighted that resistance is a polygenic trait. Several thousand genes were identified as differentially expressed between controls and infected samples, and enriched pathways related to the host immune response were highlighted. In addition, several networks with significant correlation with SRS resistance breeding values were identified, suggesting their involvement in mediating genetic resistance. These included apoptosis, cytoskeletal organisation, and the inflammasome. CONCLUSIONS: While resistance to SRS is a polygenic trait, this study has highlighted several relevant networks and genes that are likely to play a role in mediating genetic resistance. These genes may be future targets for functional studies, including genome editing, to further elucidate their role underpinning genetic variation in host resistance. | 2021 | 33676414 |
| 9657 | 3 | 0.9980 | Machine 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. | 2018 | 29359195 |
| 3881 | 4 | 0.9980 | Meta-transcriptomics reveals a diverse antibiotic resistance gene pool in avian microbiomes. BACKGROUND: Antibiotic resistance is rendering common bacterial infections untreatable. Wildlife can incorporate and disperse antibiotic-resistant bacteria in the environment, such as water systems, which in turn serve as reservoirs of resistance genes for human pathogens. Anthropogenic activity may contribute to the spread of bacterial resistance cycling through natural environments, including through the release of human waste, as sewage treatment only partially removes antibiotic-resistant bacteria. However, empirical data supporting these effects are currently limited. Here we used bulk RNA-sequencing (meta-transcriptomics) to assess the diversity and expression levels of functionally viable resistance genes in the gut microbiome of birds with aquatic habits in diverse locations. RESULTS: We found antibiotic resistance genes in birds from all localities, from penguins in Antarctica to ducks in a wastewater treatment plant in Australia. Comparative analysis revealed that birds feeding at the wastewater treatment plant carried the greatest resistance gene burden, including genes typically associated with multidrug resistance plasmids as the aac(6)-Ib-cr gene. Differences in resistance gene burden also reflected aspects of bird ecology, taxonomy, and microbial function. Notably, ducks, which feed by dabbling, carried a higher abundance and diversity of resistance genes than turnstones, avocets, and penguins, which usually prey on more pristine waters. CONCLUSIONS: These transcriptome data suggest that human waste, even if it undergoes treatment, might contribute to the spread of antibiotic resistance genes to the wild. Differences in microbiome functioning across different bird lineages may also play a role in the antibiotic resistance burden carried by wild birds. In summary, we reveal the complex factors explaining the distribution of resistance genes and their exchange routes between humans and wildlife, and show that meta-transcriptomics is a valuable tool to access functional resistance genes in whole microbial communities. | 2019 | 30961590 |
| 7705 | 5 | 0.9980 | Oxytetracycline 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. | 2018 | 30594143 |
| 7691 | 6 | 0.9980 | Antimicrobial Chemicals Associate with Microbial Function and Antibiotic Resistance Indoors. Humans purposefully and inadvertently introduce antimicrobial chemicals into buildings, resulting in widespread compounds, including triclosan, triclocarban, and parabens, in indoor dust. Meanwhile, drug-resistant infections continue to increase, raising concerns that buildings function as reservoirs of, or even select for, resistant microorganisms. Support for these hypotheses is limited largely since data describing relationships between antimicrobials and indoor microbial communities are scant. We combined liquid chromatography-isotope dilution tandem mass spectrometry with metagenomic shotgun sequencing of dust collected from athletic facilities to characterize relationships between indoor antimicrobial chemicals and microbial communities. Elevated levels of triclosan and triclocarban, but not parabens, were associated with distinct indoor microbiomes. Dust of high triclosan content contained increased Gram-positive species with diverse drug resistance capabilities, whose pangenomes were enriched for genes encoding osmotic stress responses, efflux pump regulation, lipid metabolism, and material transport across cell membranes; such triclosan-associated functional shifts have been documented in laboratory cultures but not yet from buildings. Antibiotic-resistant bacterial isolates were cultured from all but one facility, and resistance often increased in buildings with very high triclosan levels, suggesting links between human encounters with viable drug-resistant bacteria and local biocide conditions. This characterization uncovers complex relationships between antimicrobials and indoor microbiomes: some chemicals elicit effects, whereas others may not, and no single functional or resistance factor explained chemical-microbe associations. These results suggest that anthropogenic chemicals impact microbial systems in or around buildings and their occupants, highlighting an emergent need to identify the most important indoor, outdoor, and host-associated sources of antimicrobial chemical-resistome interactions. IMPORTANCE The ubiquitous use of antimicrobial chemicals may have undesired consequences, particularly on microbes in buildings. This study shows that the taxonomy and function of microbes in indoor dust are strongly associated with antimicrobial chemicals-more so than any other feature of the buildings. Moreover, we identified links between antimicrobial chemical concentrations in dust and culturable bacteria that are cross-resistant to three clinically relevant antibiotics. These findings suggest that humans may be influencing the microbial species and genes that are found indoors through the addition and removal of particular antimicrobial chemicals. | 2018 | 30574558 |
| 4379 | 7 | 0.9980 | Drug resistance in Chromobacterium violaceum. Chromobacterium violaceum is a free-living bacterium commonly found in aquatic habitats of tropical and subtropical regions of the world. This bacterium is able to produce a large variety of products of biotechnological and pharmacological use. Although C. violaceum is considered to be non-pathogenic, some cases of severe infections in humans and other animals have been reported. Genomic data on the type strain ATCC 12472(T) has provided a comprehensive basis for detailed studies of pathogenicity, virulence and drug resistance genes. A large number of open reading frames associated with various mechanisms of drug resistance were found, comprising a remarkable feature of this organism. Amongst these, beta-lactam (penicillin and cephalosporin) and multidrug resistance genes (drug efflux pumps) were the most numerous. In addition, genes associated with bacitracin, bicyclomycin, chloramphenicol, kasugamycin, and methylenomycin were also found. It is postulated that these genes contribute to the ability of C. violaceum to compete with other bacteria in the environment, and also may help to explain the common drug resistance phenotypes observed in infections caused by this bacterium. | 2004 | 15100994 |
| 8932 | 8 | 0.9980 | Alternative Evolutionary Paths to Bacterial Antibiotic Resistance Cause Distinct Collateral Effects. When bacteria evolve resistance against a particular antibiotic, they may simultaneously gain increased sensitivity against a second one. Such collateral sensitivity may be exploited to develop novel, sustainable antibiotic treatment strategies aimed at containing the current, dramatic spread of drug resistance. To date, the presence and molecular basis of collateral sensitivity has only been studied in few bacterial species and is unknown for opportunistic human pathogens such as Pseudomonas aeruginosa. In the present study, we assessed patterns of collateral effects by experimentally evolving 160 independent populations of P. aeruginosa to high levels of resistance against eight commonly used antibiotics. The bacteria evolved resistance rapidly and expressed both collateral sensitivity and cross-resistance. The pattern of such collateral effects differed to those previously reported for other bacterial species, suggesting interspecific differences in the underlying evolutionary trade-offs. Intriguingly, we also identified contrasting patterns of collateral sensitivity and cross-resistance among the replicate populations adapted to the same drug. Whole-genome sequencing of 81 independently evolved populations revealed distinct evolutionary paths of resistance to the selective drug, which determined whether bacteria became cross-resistant or collaterally sensitive towards others. Based on genomic and functional genetic analysis, we demonstrate that collateral sensitivity can result from resistance mutations in regulatory genes such as nalC or mexZ, which mediate aminoglycoside sensitivity in β-lactam-adapted populations, or the two-component regulatory system gene pmrB, which enhances penicillin sensitivity in gentamicin-resistant populations. Our findings highlight substantial variation in the evolved collateral effects among replicates, which in turn determine their potential in antibiotic therapy. | 2017 | 28541480 |
| 8414 | 9 | 0.9979 | Patterns of Piscirickettsia salmonis load in susceptible and resistant families of Salmo salar. The pathogen Piscirickettsia salmonis produces a systemic aggressive infection that involves several organs and tissues in salmonids. In spite of the great economic losses caused by this pathogen in the Atlantic salmon (Salmo salar) industry, very little is known about the resistance mechanisms of the host to this pathogen. In this paper, for the first time, we aimed to identify the bacterial load in head kidney and muscle of Atlantic salmon exhibiting differential familiar mortality. Furthermore, in order to assess the patterns of gene expression of immune related genes in susceptible and resistant families, a set of candidate genes was evaluated using deep sequencing of the transcriptome. The results showed that the bacterial load was significantly lower in resistant fish, when compared with the susceptible individuals. Based on the candidate genes analysis, we infer that the resistant hosts triggered up-regulation of specific genes (such as for example the LysC), which may explain a decrease in the bacterial load in head kidney, while the susceptible fish presented an exacerbated innate response, which is unable to exert an effective response against the bacteria. Interestingly, we found a higher bacterial load in muscle when compared with head kidney. We argue that this is possible due to the availability of an additional source of iron in muscle. Besides, the results show that the resistant fish could not be a likely reservoir of the bacteria. | 2015 | 25862974 |
| 7708 | 10 | 0.9979 | Dietary impact on the gut resistome: western diet independently increases the prevalence of antibiotic resistance genes within the gut microbiota. Approximately half of surgical site infections are caused by pathogens resistant to the antibiotics used for prophylaxis. We recently demonstrated that when mice are fed a western diet (WD) that is high in fat and low in fiber, exposed to antibiotics, and undergo an otherwise recoverable surgery, they develop lethal sepsis associated with dissemination of multi-drug-resistant pathogens. Here, we hypothesized that a WD alone can drive the intestinal microbiome to become populated by antibiotic-resistant bacteria independent of exposure to antibiotics. The cecal microbiota response to antibiotics was determined utilizing Biolog Phenotype Microarrays in the presence of 48 different antibiotics. WD-fed mice had a significant increase in antibiotic resistance within their microbiome compared to mice on a standard low-fat, high-fiber diet (SD) including aminoglycosides, tetracyclines, cephalosporins, fluoroquinolones, and sulfamethoxazole. By metagenomic sequencing, there was an increase in the antibiotic resistance genes (ARGs) within the WD cecal microbiota, including CfxA2, ErmG, TetQ, and LnuC. After just 7 days of WD, the ARGs ErmG and CfxA2 were detectable within the stool. WD independent of antibiotic exposure increases the presence of ARGs within the gut microbiota independent of antibiotic exposure.IMPORTANCEAntibiotic resistance is a major challenge in healthcare and results in significant morbidity and mortality. Currently, half of surgical site infections are caused by pathogens resistant to antibiotics used for prophylaxis. In this study, we demonstrate that a western diet alone has the ability to increase the presence of antibiotic resistance genes within the gut microbiome. By understanding dietary influences on the gut resistome, we may improve our understanding of infections with antibiotic-resistant organisms and one day develop personalized antibiotic regimens based on an individual's gut resistome. | 2025 | 40719501 |
| 9661 | 11 | 0.9979 | Pangenomes of human gut microbiota uncover links between genetic diversity and stress response. The genetic diversity of the gut microbiota has a central role in host health. Here, we created pangenomes for 728 human gut prokaryotic species, quadrupling the genes of strain-specific genomes. Each of these species has a core set of a thousand genes, differing even between closely related species, and an accessory set of genes unique to the different strains. Functional analysis shows high strain variability associates with sporulation, whereas low variability is linked with antibiotic resistance. We further map the antibiotic resistome across the human gut population and find 237 cases of extreme resistance even to last-resort antibiotics, with a predominance among Enterobacteriaceae. Lastly, the presence of specific genes in the microbiota relates to host age and sex. Our study underscores the genetic complexity of the human gut microbiota, emphasizing its significant implications for host health. The pangenomes and antibiotic resistance map constitute a valuable resource for further research. | 2024 | 39353429 |
| 8382 | 12 | 0.9979 | Transcriptional and Functional Analysis of Bifidobacterium animalis subsp. lactis Exposure to Tetracycline. Commercial probiotic bacteria must be tested for acquired antibiotic resistance elements to avoid potential transfer to pathogens. The European Food Safety Authority recommends testing resistance using microdilution culture techniques previously used to establish inhibitory thresholds for the Bifidobacterium genus. Many Bifidobacterium animalis subsp. lactis strains exhibit increased resistance to tetracycline, historically attributed to the ribosomal protection gene tet(W). However, some strains that harbor genetically identical tet(W) genes show various inhibition levels, suggesting that other genetic elements also contribute to observed differences. Here, we adapted several molecular assays to confirm the inhibition of B. animalis subsp. lactis strains Bl-04 and HN019 and employed RNA sequencing to assess the transcriptional differences related to genomic polymorphisms. We detected specific stress responses to the antibiotic by correlating ATP concentration to number of viable genome copies from droplet digital PCR and found that the bacteria were still metabolically active in high drug concentrations. Transcriptional analyses revealed that several polymorphic regions, particularly a novel multidrug efflux transporter, were differentially expressed between the strains in each experimental condition, likely having phenotypic effects. We also found that the tet(W) gene was upregulated only during subinhibitory tetracycline concentrations, while two novel tetracycline resistance genes were upregulated at high concentrations. Furthermore, many genes involved in amino acid metabolism and transporter function were upregulated, while genes for complex carbohydrate utilization, protein metabolism, and clustered regularly interspaced short palindromic repeat(s) (CRISPR)-Cas systems were downregulated. These results provide high-throughput means for assessing antibiotic resistances of two highly related probiotic strains and determine the genetic network that contributes to the global tetracycline response.IMPORTANCEBifidobacterium animalis subsp. lactis is widely used in human food and dietary supplements. Although well documented to be safe, B. animalis subsp. lactis strains must not contain transferable antibiotic resistance elements. Many B. animalis subsp. lactis strains have different resistance measurements despite being genetically similar, and the reasons for this are not well understood. In the current study, we sought to examine how genomic differences between two closely related industrial B. animalis subsp. lactis strains contribute to different resistance levels. This will lead to a better understanding of resistance, identify future targets for analysis of transferability, and expand our understanding of tetracycline resistance in bacteria. | 2018 | 30266728 |
| 8667 | 13 | 0.9979 | Glacier-Fed Stream Biofilms Harbor Diverse Resistomes and Biosynthetic Gene Clusters. Antimicrobial resistance (AMR) is a universal phenomenon the origins of which lay in natural ecological interactions such as competition within niches, within and between micro- to higher-order organisms. To study these phenomena, it is crucial to examine the origins of AMR in pristine environments, i.e., limited anthropogenic influences. In this context, epilithic biofilms residing in glacier-fed streams (GFSs) are an excellent model system to study diverse, intra- and inter-domain, ecological crosstalk. We assessed the resistomes of epilithic biofilms from GFSs across the Southern Alps (New Zealand) and the Caucasus (Russia) and observed that both bacteria and eukaryotes encoded twenty-nine distinct AMR categories. Of these, beta-lactam, aminoglycoside, and multidrug resistance were both abundant and taxonomically distributed in most of the bacterial and eukaryotic phyla. AMR-encoding phyla included Bacteroidota and Proteobacteria among the bacteria, alongside Ochrophyta (algae) among the eukaryotes. Additionally, biosynthetic gene clusters (BGCs) involved in the production of antibacterial compounds were identified across all phyla in the epilithic biofilms. Furthermore, we found that several bacterial genera (Flavobacterium, Polaromonas, Superphylum Patescibacteria) encode both atimicrobial resistance genes (ARGs) and BGCs within close proximity of each other, demonstrating their capacity to simultaneously influence and compete within the microbial community. Our findings help unravel how naturally occurring BGCs and AMR contribute to the epilithic biofilms mode of life in GFSs. Additionally, we report that eukaryotes may serve as AMR reservoirs owing to their potential for encoding ARGs. Importantly, these observations may be generalizable and potentially extended to other environments that may be more or less impacted by human activity. IMPORTANCE Antimicrobial resistance is an omnipresent phenomenon in the anthropogenically influenced ecosystems. However, its role in shaping microbial community dynamics in pristine environments is relatively unknown. Using metagenomics, we report the presence of antimicrobial resistance genes and their associated pathways in epilithic biofilms within glacier-fed streams. Importantly, we observe biosynthetic gene clusters associated with antimicrobial resistance in both pro- and eukaryotes in these biofilms. Understanding the role of resistance in the context of this pristine environment and complex biodiversity may shed light on previously uncharacterized mechanisms of cross-domain interactions. | 2023 | 36688698 |
| 8917 | 14 | 0.9979 | Evolutionary responses of Escherichia coli to phage pressure: insights into mucoidy and colanic acid overexpression. BACKGROUND: Antibiotic resistance is a major issue affecting all spheres of human activity, including agriculture. One significant example is the Avian Pathogenic Escherichia coli (APEC), a bacterium that infects poultry and leads to substantial economic losses in the farming industry. As antibiotics lose efficacity, bacteriophages (phages) -viruses that specifically target bacteria-are emerging as a promising alternative to antibiotics for treating and preventing bacterial infections. However, bacteria can develop resistance to phages through various mechanisms. Studying the coevolution between a phage and its host bacterium is important to gain insight into the phage's potential as a therapeutic agent. This study investigates the evolutionary responses of an APEC strain and a laboratory E. coli strain to a commercial phage originally isolated from APEC. RESULTS: In most cases, phage resistance resulted in a significant increase in mucoidy. Genomic analysis revealed that this resistance consistently correlated with amino acid changes, particularly in proteins involved in colanic acid production, such as YrfF. Further investigation of a mutation found in the YrfF protein demonstrated that this mutation altered the protein's structure and its interaction with the membrane. Transcriptomic analysis confirmed that the genes involved in colanic acid production were significantly overexpressed. Although the strains possessed a CRISPR-Cas system, it did not contribute to phage resistance. CONCLUSIONS: This study suggests that specific amino acid changes in key proteins may be a mechanism employed by E. coli, including APEC, to defend against phage infections. | 2025 | 40329173 |
| 4269 | 15 | 0.9979 | Whole-cell modeling of E. coli colonies enables quantification of single-cell heterogeneity in antibiotic responses. Antibiotic resistance poses mounting risks to human health, as current antibiotics are losing efficacy against increasingly resistant pathogenic bacteria. Of particular concern is the emergence of multidrug-resistant strains, which has been rapid among Gram-negative bacteria such as Escherichia coli. A large body of work has established that antibiotic resistance mechanisms depend on phenotypic heterogeneity, which may be mediated by stochastic expression of antibiotic resistance genes. The link between such molecular-level expression and the population levels that result is complex and multi-scale. Therefore, to better understand antibiotic resistance, what is needed are new mechanistic models that reflect single-cell phenotypic dynamics together with population-level heterogeneity, as an integrated whole. In this work, we sought to bridge single-cell and population-scale modeling by building upon our previous experience in "whole-cell" modeling, an approach which integrates mathematical and mechanistic descriptions of biological processes to recapitulate the experimentally observed behaviors of entire cells. To extend whole-cell modeling to the "whole-colony" scale, we embedded multiple instances of a whole-cell E. coli model within a model of a dynamic spatial environment, allowing us to run large, parallelized simulations on the cloud that contained all the molecular detail of the previous whole-cell model and many interactive effects of a colony growing in a shared environment. The resulting simulations were used to explore the response of E. coli to two antibiotics with different mechanisms of action, tetracycline and ampicillin, enabling us to identify sub-generationally-expressed genes, such as the beta-lactamase ampC, which contributed greatly to dramatic cellular differences in steady-state periplasmic ampicillin and was a significant factor in determining cell survival. | 2023 | 37327241 |
| 3868 | 16 | 0.9979 | Warming is Associated With More Encoded Antimicrobial Resistance Genes and Transcriptions Within Five Drug Classes in Soil Bacteria: A Case Study and Synthesis. The effect of warming on anti-microbial resistance (AMR) genes in the environment has critical implications for public health but is little studied. We collected published soil bacterial genomes from the BV-BRC database and tested the correlation between reported optimal growth temperature and the number of encoded AMR genes. Furthermore, we tested the relationship between temperature and AMR gene transcription in a natural ecosystem by analysing soil transcriptomes from a warming manipulation experiment in an Alaskan boreal forest. We hypothesised that there is a positive relationship between warming and AMR prevalence in gene content in bacterial genomes and transcriptomic sequences, and that this effect would vary by drug class. Regarding the bacterial genomes, we found a positive relationship between the fraction of encoded AMR genes and the reported optimal temperature of soil bacteria. The drug classes tetracycline and lincosamide/macrolide/streptogramin had the strongest positive relationship with reported optimal temperature. For the case study in a natural ecosystem, we found 61 significantly upregulated AMR gene-associated transcripts spanning eight drug classes in warmed plots. In the Alaskan soil samples, we found that warming elicited the strongest positive effect on transcripts targeting lincosamide/streptogramin, beta-lactam and phenicol/quinolone antibiotics. Overall, higher temperatures were linked to AMR gene prevalence. | 2025 | 40262767 |
| 9605 | 17 | 0.9979 | Gene Expression Variability Underlies Adaptive Resistance in Phenotypically Heterogeneous Bacterial Populations. The root cause of the antibiotic resistance crisis is the ability of bacteria to evolve resistance to a multitude of antibiotics and other environmental toxins. The regulation of adaptation is difficult to pinpoint due to extensive phenotypic heterogeneity arising during evolution. Here, we investigate the mechanisms underlying general bacterial adaptation by evolving wild-type Escherichia coli populations to dissimilar chemical toxins. We demonstrate the presence of extensive inter- and intrapopulation phenotypic heterogeneity across adapted populations in multiple traits, including minimum inhibitory concentration, growth rate, and lag time. To search for a common response across the heterogeneous adapted populations, we measured gene expression in three stress-response networks: the mar regulon, the general stress response, and the SOS response. While few genes were differentially expressed, clustering revealed that interpopulation gene expression variability in adapted populations was distinct from that of unadapted populations. Notably, we observed both increases and decreases in gene expression variability upon adaptation. Sequencing select genes revealed that the observed gene expression trends are not necessarily attributable to genetic changes. To further explore the connection between gene expression variability and adaptation, we propagated single-gene knockout and CRISPR (clustered regularly interspaced short palindromic repeats) interference strains and quantified impact on adaptation to antibiotics. We identified significant correlations that suggest genes with low expression variability have greater impact on adaptation. This study provides evidence that gene expression variability can be used as an indicator of bacterial adaptive resistance, even in the face of the pervasive phenotypic heterogeneity underlying adaptation. | 2015 | 27623410 |
| 3830 | 18 | 0.9979 | Resistance Gene Carriage Predicts Growth of Natural and Clinical Escherichia coli Isolates in the Absence of Antibiotics. Bacterial pathogens that carry antibiotic resistance alleles sometimes pay a cost in the form of impaired growth in antibiotic-free conditions. This cost of resistance is expected to be a key parameter for understanding how resistance spreads and persists in pathogen populations. Analysis of individual resistance alleles from laboratory evolution and natural isolates has shown they are typically costly, but these costs are highly variable and influenced by genetic variation at other loci. It therefore remains unclear how strongly resistance is linked to impaired antibiotic-free growth in bacteria from natural and clinical scenarios, where resistance alleles are likely to coincide with other types of genetic variation. To investigate this, we measured the growth of 92 natural and clinical Escherichia coli isolates across three antibiotic-free environments. We then tested whether variation of antibiotic-free growth among isolates was predicted by their resistance to 10 antibiotics, while accounting for the phylogenetic structure of the data. We found that isolates with similar resistance profiles had similar antibiotic-free growth profiles, but it was not simply that higher average resistance was associated with impaired growth. Next, we used whole-genome sequences to identify antibiotic resistance genes and found that isolates carrying a greater number of resistance gene types grew relatively poorly in antibiotic-free conditions, even when the resistance genes they carried were different. This suggests that the resistance of bacterial pathogens is linked to growth costs in nature, but it is the total genetic burden and multivariate resistance phenotype that predict these costs, rather than individual alleles or mean resistance across antibiotics.IMPORTANCE Managing the spread of antibiotic resistance in bacterial pathogens is a major challenge for global public health. Central to this challenge is understanding whether resistance is linked to impaired bacterial growth in the absence of antibiotics, because this determines whether resistance declines when bacteria are no longer exposed to antibiotics. We studied 92 isolates of the key bacterial pathogen Escherichia coli; these isolates varied in both their antibiotic resistance genes and other parts of the genome. Taking this approach, rather than focusing on individual genetic changes associated with resistance as in much previous work, revealed that growth without antibiotics was linked to the number of specialized resistance genes carried and the combination of antibiotics to which isolates were resistant but was not linked to average antibiotic resistance. This approach provides new insights into the genetic factors driving the long-term persistence of antibiotic-resistant bacteria, which is important for future efforts to predict and manage resistance. | 2019 | 30530714 |
| 8913 | 19 | 0.9979 | The gut environment regulates bacterial gene expression which modulates susceptibility to bacteriophage infection. Abundance and diversity of bacteria and their viral predators, bacteriophages (phages), in the digestive tract are associated with human health. Particularly intriguing is the long-term coexistence of these two antagonistic populations. We performed genome-wide RNA sequencing on a human enteroaggregative Escherichia coli isolate to identify genes differentially expressed between in vitro conditions and in murine intestines. We experimentally demonstrated that four of these differentially expressed genes modified the interactions between E. coli and three virulent phages by either increasing or decreasing its susceptibility/resistance pattern and also by interfering with biofilm formation. Therefore, the regulation of bacterial genes expression during the colonization of the digestive tract influences the coexistence of phages and bacteria, highlighting the intricacy of tripartite relationships between phages, bacteria, and the animal host in intestinal homeostasis. | 2022 | 35421351 |