# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 8766 | 0 | 0.9967 | Partitioning the Effects of Soil Legacy and Pathogen Exposure Determining Soil Suppressiveness via Induced Systemic Resistance. Beneficial host-associated bacteria can assist plant protection against pathogens. In particular, specific microbes are able to induce plant systemic resistance. However, it remains largely elusive which specific microbial taxa and functions trigger plant immune responses associated with disease suppression. Here, we experimentally studied this by setting up two independent microcosm experiments that differed in the time at which plants were exposed to the pathogen and the soil legacy (i.e., soils with historically suppressive or conducive). Overall, we found soil legacy effects to have a major influence on disease suppression irrespective of the time prior to pathogen exposure. Rhizosphere bacterial communities of tomato plants were significantly different between the two soils, with potential beneficial strains occurring at higher relative abundances in the suppressive soil. Root transcriptome analysis revealed the soil legacy to induce differences in gene expression, most importantly, genes involved in the pathway of phenylpropanoid biosynthesis. Last, we found genes in the phenylpropanoid biosynthesis pathway to correlate with specific microbial taxa, including Gp6, Actinomarinicola, Niastella, Phaeodactylibacter, Longimicrobium, Bythopirellula, Brevundimonas, Ferruginivarius, Kushneria, Methylomarinovum, Pseudolabrys, Sphingobium, Sphingomonas, and Alterococcus. Taken together, our study points to the potential regulation of plant systemic resistance by specific microbial taxa, and the importance of soil legacy on disease incidence and eliciting plant-defense mechanisms. | 2022 | 36365269 |
| 665 | 1 | 0.9967 | Functional versatility of Zur in metal homeostasis, motility, biofilm formation, and stress resistance in Yersinia pseudotuberculosis. Zur (zinc uptake regulator) is a significant member of the Fur (ferric uptake regulator) superfamily, which is widely distributed in bacteria. Zur plays crucial roles in zinc homeostasis and influences cell development and environmental adaptation in various species. Yersinia pseudotuberculosis is a Gram-negative enteric that pathogen usually serves as a model organism in pathogenicity studies. The regulatory effects of Zur on the zinc transporter ZnuABC and the protein secretion system T6SS have been documented in Y. pseudotuberculosis. In this study, a comparative transcriptomics analysis between a ∆zur mutant and the wild-type (WT) strain of Y. pseudotuberculosis was conducted using RNA-seq. This analysis revealed global regulation by Zur across multiple functional categories, including membrane transport, cell motility, and molecular and energy metabolism. Additionally, Zur mediates the homeostasis not only of zinc but also ferric and magnesium in vivo. There was a notable decrease in 35 flagellar biosynthesis and assembly-related genes, leading to reduced swimming motility in the ∆zur mutant strain. Furthermore, Zur upregulated multiple simple sugar and oligopeptide transport system genes by directly binding to their promoters. The absence of Zur inhibited biofilm formation as well as reduced resistance to chloramphenicol and acidic stress. This study illustrates the comprehensive regulatory functions of Zur, emphasizing its importance in stress resistance and pathogenicity in Y. pseudotuberculosis. IMPORTANCE: Bacteria encounter diverse stresses in the environment and possess essential regulators to modulate the expression of genes in responding to the stresses for better fitness and survival. Zur (zinc uptake regulator) plays a vital role in zinc homeostasis. Studies of Zur from multiple species reviewed that it influences cell development, stress resistance, and virulence of bacteria. Y. pseudotuberculosis is an enteric pathogen that serves a model organism in the study of pathogenicity, virulence factors, and mechanism of environmental adaptation. In this study, transcriptomics analysis of Zur's regulons was conducted in Y. pseudotuberculosis. The functions of Zur as a global regulator in metal homeostasis, motility, nutrient acquisition, glycan metabolism, and nucleotide metabolism, in turn, increasing the biofilm formation, stress resistance, and virulence were reviewed. The importance of Zur in environmental adaptation and pathogenicity of Y. pseudotuberculosis was emphasized. | 2024 | 38534119 |
| 8329 | 2 | 0.9965 | Protozoan predation enhances stress resistance and antibiotic tolerance in Burkholderia cenocepacia by triggering the SOS response. Bacterivorous protists are thought to serve as training grounds for bacterial pathogens by subjecting them to the same hostile conditions that they will encounter in the human host. Bacteria that survive intracellular digestion exhibit enhanced virulence and stress resistance after successful passage through protozoa but the underlying mechanisms are unknown. Here we show that the opportunistic pathogen Burkholderia cenocepacia survives phagocytosis by ciliates found in domestic and hospital sink drains, and viable bacteria are expelled packaged in respirable membrane vesicles with enhanced resistance to oxidative stress, desiccation, and antibiotics, thereby contributing to pathogen dissemination in the environment. Reactive oxygen species generated within the protozoan phagosome promote the formation of persisters tolerant to ciprofloxacin by activating the bacterial SOS response. In addition, we show that genes encoding antioxidant enzymes are upregulated during passage through ciliates increasing bacterial resistance to oxidative radicals. We prove that suppression of the SOS response impairs bacterial intracellular survival and persister formation within protists. This study highlights the significance of protozoan food vacuoles as niches that foster bacterial adaptation in natural and built environments and suggests that persister switch within phagosomes may be a widespread phenomenon in bacteria surviving intracellular digestion. | 2024 | 38366016 |
| 8658 | 3 | 0.9964 | Microplastic exposure reshapes the virome and virus-bacteria networks with implications for immune regulation in Mytilus coruscus. Microplastic pollution has emerged as a critical environmental concern, yet its impacts on host-associated viral communities and immune balance in marine bivalves remain largely unexplored. In this study, Mytilus coruscus individuals were exposed to microplastics in situ for seven days. Virome sequencing and bioinformatic analyses revealed that microplastic exposure induced divergent responses in DNA and RNA viral communities. DNA viromes exhibited suppressed diversity and downregulation of core viral metabolic pathways, potentially reflecting reduced viral replication capacity under host immune stress. In contrast, RNA viromes displayed metabolic activation and functional shifts, including enriched glycan and nucleotide metabolism, possibly linked to enhanced viral activity or immune evasion. Phage-bacteria interaction networks were also restructured, showing increased associations with opportunistic pathogens such as Vibrio cholerae and Enterobacter, potentially affecting immune surveillance. Furthermore, the expression of antibiotic resistance genes (ARGs) in viral genomes was differentially regulated, suggesting pollutant-induced microbial selection that may challenge host immune resilience. These findings suggest that microplastics not only reshape virome composition and metabolic functions but also influence virus-mediated immune interactions, with important implications for disease susceptibility and immune homeostasis in filter-feeding shellfish. | 2025 | 41056669 |
| 8296 | 4 | 0.9964 | Transcriptional Response of Burkholderia cenocepacia H111 to Severe Zinc Starvation. Burkholderia cenocepacia is an opportunistic pathogen that is primarily associated with severe respiratory infections in people with cystic fibrosis. These bacteria have significant intrinsic resistance to antimicrobial therapy, and there is a need for more effective treatments. Bacterial zinc uptake and homeostasis systems are attractive targets for new drugs, yet our understanding of how bacteria acquire and utilise zinc remains incomplete. Here we have used RNA-sequencing and differential gene expression analysis to investigate how B. cenocepacia H111 is able to survive in zinc poor environments, such as those expected to be encountered within the host. The data shows that 201 genes are significantly differentially expressed when zinc supply is severely limited. Included in the 85 upregulated genes, are genes encoding a putative ZnuABC high affinity zinc importer, two TonB-dependent outer membrane receptors that may facilitate zinc uptake across the outer cell membrane, and a COG0523 family zinc metallochaperone. Amongst the 116 downregulated genes, are several zinc-dependent enzymes suggesting a mechanism of zinc sparring to reduce the cells demand for zinc when bioavailability is low. | 2023 | 37822354 |
| 589 | 5 | 0.9964 | Insulin Signaling and Insulin Resistance Facilitate Trained Immunity in Macrophages Through Metabolic and Epigenetic Changes. Adaptation of the innate immune system has been recently acknowledged, explaining sustained changes of innate immune responses. Such adaptation is termed trained immunity. Trained immunity is initiated by extracellular signals that trigger a cascade of events affecting cell metabolism and mediating chromatin changes on genes that control innate immune responses. Factors demonstrated to facilitate trained immunity are pathogenic signals (fungi, bacteria, viruses) as well non-pathogenic signals such as insulin, cytokines, adipokines or hormones. These signals initiate intracellular signaling cascades that include AKT kinases and mTOR as well as histone methylases and demethylases, resulting in metabolic changes and histone modifications. In the context of insulin resistance, AKT signaling is affected resulting in sustained activation of mTORC1 and enhanced glycolysis. In macrophages elevated glycolysis readily impacts responses to pathogens (bacteria, fungi) or danger signals (TLR-driven signals of tissue damage), partly explaining insulin resistance-related pathologies. Thus, macrophages lacking insulin signaling exhibit reduced responses to pathogens and altered metabolism, suggesting that insulin resistance is a state of trained immunity. Evidence from Insulin Receptor as well as IGF1Receptor deficient macrophages support the contribution of insulin signaling in macrophage responses. In addition, clinical evidence highlights altered macrophage responses to pathogens or metabolic products in patients with systemic insulin resistance, being in concert with cell culture and animal model studies. Herein, we review the current knowledge that supports the impact of insulin signaling and other insulin resistance related signals as modulators of trained immunity. | 2019 | 31244863 |
| 742 | 6 | 0.9963 | Mutations in Salmonella pathogenicity island 2 (SPI2) genes affecting transcription of SPI1 genes and resistance to antimicrobial agents. The Salmonella typhimurium genome contains two pathogenicity islands (SPI) with genes encoding type III secretion systems for virulence proteins. SPI1 is required for the penetration of the epithelial layer of the intestine. SPI2 is important for the subsequent proliferation of bacteria in the spleens of infected hosts. Although most mutations in SPI2 lead to a strong reduction of virulence, they have different effects in vitro, with some mutants having significantly increased sensitivity to gentamicin and the antibacterial peptide polymyxin B. Previously we showed that certain mutations in SPI2 affect the ability of S. typhimurium to secrete SPI1 effector proteins and to invade cultured eukaryotic cells. In this study, we show that these SPI2 mutations affect the expression of the SPI1 invasion genes. Analysis of reporter fusions to various SPI1 genes reveals highly reduced expression of sipC, prgK, and hilA, the transcriptional activator of SPI1 genes. These observations indicate that the expression of one type III secretion system can be influenced dramatically by mutations in genes encoding a second type III secretion system in the same cell. | 1998 | 9733677 |
| 9240 | 7 | 0.9963 | CRISPR-Cas-Mediated Phage Resistance Enhances Horizontal Gene Transfer by Transduction. A powerful contributor to prokaryotic evolution is horizontal gene transfer (HGT) through transformation, conjugation, and transduction, which can be advantageous, neutral, or detrimental to fitness. Bacteria and archaea control HGT and phage infection through CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) adaptive immunity. Although the benefits of resisting phage infection are evident, this can come at a cost of inhibiting the acquisition of other beneficial genes through HGT. Despite the ability of CRISPR-Cas to limit HGT through conjugation and transformation, its role in transduction is largely overlooked. Transduction is the phage-mediated transfer of bacterial DNA between cells and arguably has the greatest impact on HGT. We demonstrate that in Pectobacterium atrosepticum, CRISPR-Cas can inhibit the transduction of plasmids and chromosomal loci. In addition, we detected phage-mediated transfer of a large plant pathogenicity genomic island and show that CRISPR-Cas can inhibit its transduction. Despite these inhibitory effects of CRISPR-Cas on transduction, its more common role in phage resistance promotes rather than diminishes HGT via transduction by protecting bacteria from phage infection. This protective effect can also increase transduction of phage-sensitive members of mixed populations. CRISPR-Cas systems themselves display evidence of HGT, but little is known about their lateral dissemination between bacteria and whether transduction can contribute. We show that, through transduction, bacteria can acquire an entire chromosomal CRISPR-Cas system, including cas genes and phage-targeting spacers. We propose that the positive effect of CRISPR-Cas phage immunity on enhancing transduction surpasses the rarer cases where gene flow by transduction is restricted.IMPORTANCE The generation of genetic diversity through acquisition of DNA is a powerful contributor to microbial evolution and occurs through transformation, conjugation, and transduction. Of these, transduction, the phage-mediated transfer of bacterial DNA, is arguably the major route for genetic exchange. CRISPR-Cas adaptive immune systems control gene transfer by conjugation and transformation, but transduction has been mostly overlooked. Our results indicate that CRISPR-Cas can impede, but typically enhances the transduction of plasmids, chromosomal genes, and pathogenicity islands. By limiting wild-type phage replication, CRISPR-Cas immunity increases transduction in both phage-resistant and -sensitive members of mixed populations. Furthermore, we demonstrate mobilization of a chromosomal CRISPR-Cas system containing phage-targeting spacers by generalized transduction, which might partly account for the uneven distribution of these systems in nature. Overall, the ability of CRISPR-Cas to promote transduction reveals an unexpected impact of adaptive immunity on horizontal gene transfer, with broader implications for microbial evolution. | 2018 | 29440578 |
| 8330 | 8 | 0.9963 | Increased iron utilization and oxidative stress tolerance in a Vibrio cholerae flrA mutant confers resistance to amoeba predation. Persistence of V. cholerae in the aquatic environment contributes to the fatal diarrheal disease cholera, which remains a global health burden. In the environment, bacteria face predation pressure by heterotrophic protists such as the free-living amoeba A. castellanii. This study explores how a mutant of V. cholerae adapts to acquire essential nutrients and survive predation. Here, we observed that up-regulation of iron acquisition genes and genes regulating resistance to oxidative stress enhances pathogen fitness. Our data show that V. cholerae can defend predation to overcome nutrient limitation and oxidative stress, resulting in an enhanced survival inside the protozoan hosts. | 2023 | 37882527 |
| 8360 | 9 | 0.9963 | Genome mining of Streptomyces scabrisporus NF3 reveals symbiotic features including genes related to plant interactions. Endophytic bacteria are wide-spread and associated with plant physiological benefits, yet their genomes and secondary metabolites remain largely unidentified. In this study, we explored the genome of the endophyte Streptomyces scabrisporus NF3 for discovery of potential novel molecules as well as genes and metabolites involved in host interactions. The complete genomes of seven Streptomyces and three other more distantly related bacteria were used to define the functional landscape of this unique microbe. The S. scabrisporus NF3 genome is larger than the average Streptomyces genome and not structured for an obligate endosymbiotic lifestyle; this and the fact that can grow in R2YE media implies that it could include a soil-living stage. The genome displays an enrichment of genes associated with amino acid production, protein secretion, secondary metabolite and antioxidants production and xenobiotic degradation, indicating that S. scabrisporus NF3 could contribute to the metabolic enrichment of soil microbial communities and of its hosts. Importantly, besides its metabolic advantages, the genome showed evidence for differential functional specificity and diversification of plant interaction molecules, including genes for the production of plant hormones, stress resistance molecules, chitinases, antibiotics and siderophores. Given the diversity of S. scabrisporus mechanisms for host upkeep, we propose that these strategies were necessary for its adaptation to plant hosts and to face changes in environmental conditions. | 2018 | 29447216 |
| 8331 | 10 | 0.9963 | An activator regulates the DNA damage response and anti-phage defense networks in Moraxellaceae. DNA-damage chemicals, including many antibiotics, often induce prophage induction and phage outbreaks within microbial communities, posing a significant threat to bacterial survival. Moraxellaceae strains are clinically relevant due to their remarkable resistance to antibiotics and radiation. However, the cellular-level regulation mechanisms that underlie their DNA damage response and anti-phage defense remain extensively unexplored. Here, we report a WYL family protein, DdaA, that has replaced the ubiquitous SOS system during the evolution of Moraxellaceae. DdaA functions as an activator and directly regulates the transcriptional networks of both DNA damage response and anti-phage defense genes under conditions of DNA damage stress. Our findings elucidate a pathway that shows how these bacteria enhance their immunity under DNA damage and shed light on controlling the resistance of Moraxellaceae strains in clinical practice. | 2025 | 40874593 |
| 9605 | 11 | 0.9963 | 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 |
| 8249 | 12 | 0.9963 | Biocontrol Traits Correlate With Resistance to Predation by Protists in Soil Pseudomonads. Root-colonizing bacteria can support plant growth and help fend off pathogens. It is clear that such bacteria benefit from plant-derived carbon, but it remains ambiguous why they invest in plant-beneficial traits. We suggest that selection via protist predation contributes to recruitment of plant-beneficial traits in rhizosphere bacteria. To this end, we examined the extent to which bacterial traits associated with pathogen inhibition coincide with resistance to protist predation. We investigated the resistance to predation of a collection of Pseudomonas spp. against a range of representative soil protists covering three eukaryotic supergroups. We then examined whether patterns of resistance to predation could be explained by functional traits related to plant growth promotion, disease suppression and root colonization success. We observed a strong correlation between resistance to predation and phytopathogen inhibition. In addition, our analysis highlighted an important contribution of lytic enzymes and motility traits to resist predation by protists. We conclude that the widespread occurrence of plant-protective traits in the rhizosphere microbiome may be driven by the evolutionary pressure for resistance against predation by protists. Protists may therefore act as microbiome regulators promoting native bacteria involved in plant protection against diseases. | 2020 | 33384680 |
| 8283 | 13 | 0.9963 | Stress responses as determinants of antimicrobial resistance in Gram-negative bacteria. Bacteria encounter a myriad of potentially growth-compromising conditions in nature and in hosts of pathogenic bacteria. These 'stresses' typically elicit protective and/or adaptive responses that serve to enhance bacterial survivability. Because they impact upon many of the same cellular components and processes that are targeted by antimicrobials, adaptive stress responses can influence antimicrobial susceptibility. In targeting and interfering with key cellular processes, antimicrobials themselves are 'stressors' to which protective stress responses have also evolved. Cellular responses to nutrient limitation (nutrient stress), oxidative and nitrosative stress, cell envelope damage (envelope stress), antimicrobial exposure and other growth-compromising stresses, have all been linked to the development of antimicrobial resistance in Gram-negative bacteria - resulting from the stimulation of protective changes to cell physiology, activation of resistance mechanisms, promotion of resistant lifestyles (biofilms), and induction of resistance mutations. | 2012 | 22424589 |
| 8310 | 14 | 0.9963 | Dynamic heterogeneity in an E. coli stress response regulon mediates gene activation and antimicrobial peptide tolerance. The bacterial stress response is an intricately regulated system that plays a critical role in cellular resistance to drug treatment. The complexity of this response is further complicated by cell-to-cell heterogeneity in the expression of bacterial stress response genes. These genes are often organized into networks comprising one or more transcriptional regulators that control expression of a suite of downstream genes. While the expression heterogeneity of many of these upstream regulators has been characterized, the way in which this variability affects the larger downstream stress response remains hard to predict, prompting two key questions. First, how does heterogeneity and expression noise in stress response regulators propagate to the diverse downstream genes in their regulons. Second, when expression levels vary, how do multiple downstream genes act together to protect cells from stress. To address these questions, we focus on the transcription factor PhoP, a critical virulence regulator which coordinates pathogenicity in several gram-negative species. We use optogenetic stimulation to precisely control PhoP expression levels and examine how variations in PhoP affect the downstream activation of genes in the PhoP regulon. We find that these downstream genes exhibit differences both in mean expression level and sensitivity to increasing levels of PhoP. These response functions can also vary between individual cells, increasing heterogeneity in the population. We tie these variations to cell survival when bacteria are exposed to a clinically-relevant antimicrobial peptide, showing that high expression of the PhoP-regulon gene pmrD provides a protective effect against Polymyxin B. Overall, we demonstrate that even subtle heterogeneity in expression of a stress response regulator can have clear consequences for enabling bacteria to survive stress. | 2024 | 39677761 |
| 9371 | 15 | 0.9962 | Coevolutionary history of predation constrains the evolvability of antibiotic resistance in prey bacteria. Understanding how the historical contingency of biotic interactions shapes the evolvability of bacterial populations is imperative for the predictability of the eco-evolutionary dynamics of microbial communities. While microbial predators like Myxococcus xanthus influence the frequency of antibiotic-resistant bacteria in nature, the effect of adaptation to the presence of predators on the evolvability of prey bacteria to future stressors is unclear. Hence, to understand the influence of the coevolutionary history of predation on the evolvability of antibiotic resistance, we propagated variants of E. coli, pre-adapted to distinct biotic and abiotic conditions, in gradually increasing concentrations of antibiotics. We show that pre-adaptation to predators limits the evolution of a high degree of antibiotic resistance. Moreover, lower degree of resistance in the evolved strains also incurs reduced fitness costs while preserving their ancestral ability to resist predation. Together, we demonstrate that the history of biotic interactions can strongly influence the evolvability of bacteria. | 2025 | 40461734 |
| 8286 | 16 | 0.9962 | RNA Modifications in Pathogenic Bacteria: Impact on Host Adaptation and Virulence. RNA modifications are involved in numerous biological processes and are present in all RNA classes. These modifications can be constitutive or modulated in response to adaptive processes. RNA modifications play multiple functions since they can impact RNA base-pairings, recognition by proteins, decoding, as well as RNA structure and stability. However, their roles in stress, environmental adaptation and during infections caused by pathogenic bacteria have just started to be appreciated. With the development of modern technologies in mass spectrometry and deep sequencing, recent examples of modifications regulating host-pathogen interactions have been demonstrated. They show how RNA modifications can regulate immune responses, antibiotic resistance, expression of virulence genes, and bacterial persistence. Here, we illustrate some of these findings, and highlight the strategies used to characterize RNA modifications, and their potential for new therapeutic applications. | 2021 | 34440299 |
| 730 | 17 | 0.9962 | How intracellular bacteria survive: surface modifications that promote resistance to host innate immune responses. Bacterial pathogens regulate the expression of virulence factors in response to environmental signals. In the case of salmonellae, many virulence factors are regulated via PhoP/PhoQ, a two-component signal transduction system that is repressed by magnesium and calcium in vitro. PhoP/PhoQ-activated genes promote intracellular survival within macrophages, whereas PhoP-repressed genes promote entrance into epithelial cells and macrophages by macropinocytosis and stimulate epithelial cell cytokine production. PhoP-activated genes include those that alter the cell envelope through structural alterations of lipopolysaccharide and lipid A, the bioactive component of lipopolysaccharide. PhoP-activated changes in the bacterial envelope likely promote intracellular survival by increasing resistance to host cationic antimicrobial peptides and decreasing host cell cytokine production. | 1999 | 10081503 |
| 9607 | 18 | 0.9962 | Transcriptome-Level Signatures in Gene Expression and Gene Expression Variability during Bacterial Adaptive Evolution. Antibiotic-resistant bacteria are an increasingly serious public health concern, as strains emerge that demonstrate resistance to almost all available treatments. One factor that contributes to the crisis is the adaptive ability of bacteria, which exhibit remarkable phenotypic and gene expression heterogeneity in order to gain a survival advantage in damaging environments. This high degree of variability in gene expression across biological populations makes it a challenging task to identify key regulators of bacterial adaptation. Here, we research the regulation of adaptive resistance by investigating transcriptome profiles of Escherichia coli upon adaptation to disparate toxins, including antibiotics and biofuels. We locate potential target genes via conventional gene expression analysis as well as using a new analysis technique examining differential gene expression variability. By investigating trends across the diverse adaptation conditions, we identify a focused set of genes with conserved behavior, including those involved in cell motility, metabolism, membrane structure, and transport, and several genes of unknown function. To validate the biological relevance of the observed changes, we synthetically perturb gene expression using clustered regularly interspaced short palindromic repeat (CRISPR)-dCas9. Manipulation of select genes in combination with antibiotic treatment promotes adaptive resistance as demonstrated by an increased degree of antibiotic tolerance and heterogeneity in MICs. We study the mechanisms by which identified genes influence adaptation and find that select differentially variable genes have the potential to impact metabolic rates, mutation rates, and motility. Overall, this work provides evidence for a complex nongenetic response, encompassing shifts in gene expression and gene expression variability, which underlies adaptive resistance. IMPORTANCE Even initially sensitive bacteria can rapidly thwart antibiotic treatment through stress response processes known as adaptive resistance. Adaptive resistance fosters transient tolerance increases and the emergence of mutations conferring heritable drug resistance. In order to extend the applicable lifetime of new antibiotics, we must seek to hinder the occurrence of bacterial adaptive resistance; however, the regulation of adaptation is difficult to identify due to immense heterogeneity emerging during evolution. This study specifically seeks to generate heterogeneity by adapting bacteria to different stresses and then examines gene expression trends across the disparate populations in order to pinpoint key genes and pathways associated with adaptive resistance. The targets identified here may eventually inform strategies for impeding adaptive resistance and prolonging the effectiveness of antibiotic treatment. | 2017 | 28217741 |
| 8285 | 19 | 0.9962 | Bacterial stress response: understanding the molecular mechanics to identify possible therapeutic targets. INTRODUCTION: Bacteria are ubiquitous and many of them are pathogenic in nature. Entry of bacteria in host and its recognition by host defense system induce stress in host cells. With time, bacteria have also developed strategies including drug resistance to escape from antibacterial therapy as well as host defense mechanism. AREAS COVERED: Bacterial stress initiates and promotes adaptive immune response through several integrated mechanisms. The mechanisms of bacteria to up and down regulate different pathways involved in these responses have been discussed. The genetic expression of these pathways can be manipulated by the pharmacological interventions. Present review discusses in these contexts and explores the possibilities to overcome stress induced by bacterial pathogens and to suggest new possible therapeutic targets. EXPERT OPINION: In our opinion, there are two important fronts to regulate the bacterial stress. One is to target caspase involved in the process of transformation and translation at gene level and protein expression. Second is the identification of bacterial genes that lead to synthesis of abnormal end products supporting bacterial survival in host environment and also to surpass the host defense mechanism. Identification of such genes and their expression products could be an effective option to encounter bacterial resistance. | 2021 | 32811215 |