Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria and Metabolites Remediates Insulin Resistance in iNOS Knockout Mice. - Related Documents




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882701.0000Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria and Metabolites Remediates Insulin Resistance in iNOS Knockout Mice. The role of oxidative and nitrosative stress has been implied in both physiology and pathophysiology of metabolic disorders. Inducible nitric oxide synthase (iNOS) has emerged as a crucial regulator of host metabolism and gut microbiota activity. The present study examines the role of the gut microbiome in determining host metabolic functions in the absence of iNOS. Insulin-resistant and dyslipidemic iNOS(-/-) mice displayed reduced microbial diversity, with a higher relative abundance of Allobaculum and Bifidobacterium, gram-positive bacteria, and altered serum metabolites along with metabolic dysregulation. Vancomycin, which largely depletes gram-positive bacteria, reversed the insulin resistance (IR), dyslipidemia, and related metabolic anomalies in iNOS(-/-) mice. Such improvements in metabolic markers were accompanied by alterations in the expression of genes involved in fatty acid synthesis in the liver and adipose tissue, lipid uptake in adipose tissue, and lipid efflux in the liver and intestine tissue. The rescue of IR in vancomycin-treated iNOS(-/-) mice was accompanied with the changes in select serum metabolites such as 10-hydroxydecanoate, indole-3-ethanol, allantoin, hippurate, sebacic acid, aminoadipate, and ophthalmate, along with improvement in phosphatidylethanolamine to phosphatidylcholine (PE/PC) ratio. In the present study, we demonstrate that vancomycin-mediated depletion of gram-positive bacteria in iNOS(-/-) mice reversed the metabolic perturbations, dyslipidemia, and insulin resistance.202135127558
878010.9989Surfactin and fengycin lipopeptides of Bacillus subtilis as elicitors of induced systemic resistance in plants. Multiple strains of Bacillus spp. were demonstrated to stimulate plant defence responses. However, very little is known about the nature of molecular determinants secreted by these Gram-positive bacteria that are responsible for the elicitation of the induced systemic resistance (ISR) phenomenon. This study shows that the lipopeptides surfactins and fengycins may be involved in this elicitation process. In bean, pure fengycins and surfactins provided a significant ISR-mediated protective effect on bean plants, similar to the one induced by living cells of the producing strain S499. Moreover, experiments conducted on bean and tomato plants showed that overexpression of both surfactin and fengycin biosynthetic genes in the naturally poor producer Bacillus subtilis strain 168 was associated with a significant increase in the potential of the derivatives to induce resistance. In tomato cells, key enzymes of the lipoxygenase pathway appeared to be activated in resistant plants following induction by lipopeptide overproducers. To our knowledge, such lipopeptides constitute a novel class of compounds from non-pathogenic bacteria that can be perceived by plant cells as signals to initiate defence mechanisms.200717359279
819620.9988The pentose phosphate pathway is essential for the resistance of Gluconacetobacter diazotrophicus PAL5 to zinc. Zinc (Zn) is an essential metal for the metabolism of bacteria, but in high concentrations, it may be toxic to cells. Gluconacetobacter diazotrophicus is a Gram-negative bacterium characterized by its ability to promote plant growth. Moreover, G. diazotrophicus can survive under challenging conditions, including metal stress. However, the mechanisms that control its resistance to metals require further investigation. This work investigated the main molecular mechanisms associated with the resistance of G. diazotrophicus PAL5 to Zn. Comparative proteomic analyses aimed to identify molecular pathways, and essential proteins were validated by mutagenesis. The main molecular pathways identified by proteomics included response to oxidative stress, sugar metabolism, nutrient uptake, cell envelope metabolism, protein quality control, and the efflux pump system. Mutagenesis showed that the absence of the genes ggt (response to oxidative stress), pgl (sugar metabolism), accC (cell envelope metabolism), tbdR (nutrient uptake), clpX and degP (protein quality control), and czcC (efflux pump system) increased the sensitivity of G. diazotrophicus mutants to Zn. Our results identified essential molecular mechanisms for Zn resistance in G. diazotrophicus, highlighting the essential role of the pentose phosphate pathway.202540999116
67730.9987Essential role of K(+) uptake permease (Kup) for resistance to sucrose-induced stress in Gluconacetobacter diazotrophicus PAl 5. Microorganisms are constantly challenged by stressful conditions, such as sugar-rich environments. Such environments can cause an imbalance of biochemical activities and compromise cell multiplication. Gluconacetobacter diazotrophicus PAl 5 is among the most sugar-tolerant bacteria, capable of growing in the presence of up to 876 mM sucrose. However, the molecular mechanisms involved in its response to high sucrose remain unknown. The present work aimed to identify sucrose-induced stress resistance genes in G. diazotrophicus PAl 5. Screening of a Tn5 transposon insertion library identified a mutant that was severely compromised in its resistance to high sucrose concentrations. Molecular characterization revealed that the mutation affected the kupA gene, which encodes a K(+) uptake transporter (KupA). Functional complementation of the mutant with the wild type kupA gene recovered the sucrose-induced stress resistance phenotype. High sucrose resistance assay, under different potassium concentrations, revealed that KupA acts as a high-affinity K(+) transporter, which is essential for resistance to sucrose-induced stress, when extracellular potassium levels are low. This study is the first to show the essential role of the KupA protein for resistance to sucrose-induced stress in bacteria by acting as a high-affinity potassium transporter in G. diazotrophicus PAl 5.201727886654
69340.9987Effect of acid adaptation on the fate of Listeria monocytogenes in THP-1 human macrophages activated by gamma interferon. In Listeria monocytogenes the acid tolerance response (ATR) takes place through a programmed molecular response which ensures cell survival under unfavorable conditions. Much evidence links ATR with virulence, but the molecular determinants involved in the reactivity to low pHs and the behavior of acid-exposed bacteria within host cells are still poorly understood. We have investigated the effect of acid adaptation on the fate of L. monocytogenes in human macrophages. Expression of genes encoding determinants for cell invasion and intracellular survival was tested for acid-exposed bacteria, and invasive behavior in the human myelomonocytic cell line THP-1 activated with gamma interferon was assessed. Functional approaches demonstrated that preexposure to an acidic pH enhances the survival of L. monocytogenes in activated human macrophages and that this effect is associated with an altered pattern of expression of genes involved in acid resistance and cell invasion. Significantly decreased transcription of the plcA gene, encoding a phospholipase C involved in vacuolar escape and cell-to-cell spread, was observed in acid-adapted bacteria. This effect was due to a reduction in the quantity of the bicistronic plcA-prfA transcript, concomitant with an increase in the level(s) of the monocistronic prfA mRNA(s). The transcriptional shift from distal to proximal prfA promoters resulted in equal levels of the prfA transcript (and, as a consequence, of the inlA, hly, and actA transcripts) under neutral and acidic conditions. In contrast, the sodC and gad genes, encoding a cytoplasmic superoxide dismutase and the glutamate-based acid resistance system, respectively, were positively regulated at a low pH. Morphological approaches confirmed the increased intracellular survival and growth of acid-adapted L. monocytogenes cells both in vacuoles and in the cytoplasm of interferon gamma-activated THP-1 macrophages. Our data indicate that preexposure to a low pH has a positive impact on subsequent challenge of L. monocytogenes with macrophagic cells.200212117947
68650.9987SigB-dependent general stress response in Bacillus subtilis and related gram-positive bacteria. One of the strongest and most noticeable responses of Bacillus subtilis cells to a range of stress and starvation stimuli is the dramatic induction of about 150 SigB-dependent general stress genes. The activity of SigB itself is tightly regulated by a complex signal transduction cascade with at least three main signaling pathways that respond to environmental stress, energy depletion, or low temperature. The SigB-dependent response is conserved in related gram-positive bacteria but is missing in strictly anaerobic or in some facultatively anaerobic gram-positive bacteria. It covers functions from nonspecific and multiple stress resistance to the control of virulence in pathogenic bacteria. A comprehensive understanding of this crucial stress response is essential not only for bacterial physiology but also for applied microbiology, including pathogenicity and pathogen control.200718035607
815060.9987ROS production during symbiotic infection suppresses pathogenesis-related gene expression. Leguminous plants have exclusive ability to form symbiotic relationship with soil bacteria of the genus Rhizobium. Symbiosis is a complex process that involves multiple molecular signaling activities, such as calcium fluxes, production of reactive oxygen species (ROS) and synthesis of nodulation genes. We analyzed the role of ROS in defense gene expression in Medicago truncatula during symbiosis and pathogenesis. Studies in Arabidopsis thaliana showed that the induction of pathogenesis-related (PR) genes during systemic acquired resistance (SAR) is regulated by NPR1 protein, which resides in the cytoplasm as an oligomer. After oxidative burst and return of reducing conditions, the NPR1 undergoes monomerization and becomes translocated to the nucleus, where it functions in PR genes induction. We show that ROS production is both stronger and longer during symbiotic interactions than during interactions with pathogenic, nonhost or common nonpathogenic soil bacteria. Moreover, root cells inoculated with Sinorhizobium meliloti accumulated ROS in the cytosol but not in vacuoles, as opposed to Pseudomonas putida inoculation or salt stress treatment. Furthermore, increased ROS accumulation by addition of H₂O₂ reduced the PR gene expression, while catalase had an opposite effect, establishing that the PR gene expression is opposite to the level of cytoplasmic ROS. In addition, we show that salicylic acid pretreatment significantly reduced ROS production in root cells during symbiotic interaction.201222499208
59570.9987Aerotolerance and peroxide resistance in peroxidase and PerR mutants of Streptococcus pyogenes. Survival in aerobic conditions is critical to the pathogenicity of many bacteria. To investigate the means of aerotolerance and resistance to oxidative stress in the catalase-negative organism Streptococcus pyogenes, we used a genomics-based approach to identify and inactivate homologues of two peroxidase genes, encoding alkyl hydroperoxidase (ahpC) and glutathione peroxidase (gpoA). Single and double mutants survived as well as the wild type under aerobic conditions. However, they were more susceptible than the wild type to growth suppression by paraquat and cumene hydroperoxide. In addition, we show that S. pyogenes demonstrates an inducible peroxide resistance response when treated with sublethal doses of peroxide. This resistance response was intact in ahpC and gpoA mutants but not in mutants lacking PerR, a repressor of several genes including ahpC and catalase (katA) in Bacillus subtilis. Because our data indicate that these peroxidase genes are not essential for aerotolerance or induced resistance to peroxide stress in S. pyogenes, genes for a novel mechanism of managing peroxide stress may be regulated by PerR in streptococci.200010986229
814880.9987Methylobacterium-plant interaction genes regulated by plant exudate and quorum sensing molecules. Bacteria from the genus Methylobacterium interact symbiotically (endophytically and epiphytically) with different plant species. These interactions can promote plant growth or induce systemic resistance, increasing plant fitness. The plant colonization is guided by molecular communication between bacteria-bacteria and bacteria-plants, where the bacteria recognize specific exuded compounds by other bacteria (e.g. homoserine molecules) and/or by the plant roots (e.g. flavonoids, ethanol and methanol), respectively. In this context, the aim of this study was to evaluate the effect of quorum sensing molecules (N-acyl-homoserine lactones) and plant exudates (including ethanol) in the expression of a series of bacterial genes involved in Methylobacterium-plant interaction. The selected genes are related to bacterial metabolism (mxaF), adaptation to stressful environment (crtI, phoU and sss), to interactions with plant metabolism compounds (acdS) and pathogenicity (patatin and phoU). Under in vitro conditions, our results showed the differential expression of some important genes related to metabolism, stress and pathogenesis, thereby AHL molecules up-regulate all tested genes, except phoU, while plant exudates induce only mxaF gene expression. In the presence of plant exudates there is a lower bacterial density (due the endophytic and epiphytic colonization), which produce less AHL, leading to down regulation of genes when compared to the control. Therefore, bacterial density, more than plant exudate, influences the expression of genes related to plant-bacteria interaction.201324688531
60390.9986Transcriptomic Analysis Reveals Adaptive Responses of an Enterobacteriaceae Strain LSJC7 to Arsenic Exposure. Arsenic (As) resistance determinant ars operon is present in many bacteria and has been demonstrated to enhance As(V) resistance of bacteria. However, whole molecular mechanism adaptations of bacteria in response to As(V) stress remain largely unknown. In this study, transcriptional profiles of Enterobacteriaceae strain LSJC7 responding to As(V) stress were analyzed using RNA-seq and qRT-PCR. As expected, genes involved in As(V) uptake were down-regulated, those involved in As(V) reduction and As(III) efflux were up-regulated, which avoided cellular As accumulation. Reactive oxygen species and nitric oxide (NO) were induced, which caused cellular damages including DNA, protein, and Fe-S cluster damage in LSJC7. The expression of specific genes encoding transcriptional regulators, such as nsrR and soxRS were also induced. NsrR and SoxRS modulated many critical metabolic activities in As(V) stressed LSJC7 cells, including reactive species scavenging and repairing damaged DNA, proteins, and Fe-S clusters. Therefore, besides As uptake, reduction, and efflux; oxidative stress defense and damage repair were the main cellular adaptive responses of LSJC7 to As(V) stress.201627199962
709100.9986Structure of the Response Regulator NsrR from Streptococcus agalactiae, Which Is Involved in Lantibiotic Resistance. Lantibiotics are antimicrobial peptides produced by Gram-positive bacteria. Interestingly, several clinically relevant and human pathogenic strains are inherently resistant towards lantibiotics. The expression of the genes responsible for lantibiotic resistance is regulated by a specific two-component system consisting of a histidine kinase and a response regulator. Here, we focused on a response regulator involved in lantibiotic resistance, NsrR from Streptococcus agalactiae, and determined the crystal structures of its N-terminal receiver domain and C-terminal DNA-binding effector domain. The C-terminal domain exhibits a fold that classifies NsrR as a member of the OmpR/PhoB subfamily of regulators. Amino acids involved in phosphorylation, dimerization, and DNA-binding were identified and demonstrated to be conserved in lantibiotic resistance regulators. Finally, a model of the full-length NsrR in the active and inactive state provides insights into protein dimerization and DNA-binding.201626930060
8149110.9986Genes related to antioxidant metabolism are involved in Methylobacterium mesophilicum-soybean interaction. The genus Methylobacterium is composed of pink-pigmented methylotrophic bacterial species that are widespread in natural environments, such as soils, stream water and plants. When in association with plants, this genus colonizes the host plant epiphytically and/or endophytically. This association is known to promote plant growth, induce plant systemic resistance and inhibit plant infection by phytopathogens. In the present study, we focused on evaluating the colonization of soybean seedling-roots by Methylobacterium mesophilicum strain SR1.6/6. We focused on the identification of the key genes involved in the initial step of soybean colonization by methylotrophic bacteria, which includes the plant exudate recognition and adaptation by planktonic bacteria. Visualization by scanning electron microscopy revealed that M. mesophilicum SR1.6/6 colonizes soybean roots surface effectively at 48 h after inoculation, suggesting a mechanism for root recognition and adaptation before this period. The colonization proceeds by the development of a mature biofilm on roots at 96 h after inoculation. Transcriptomic analysis of the planktonic bacteria (with plant) revealed the expression of several genes involved in membrane transport, thus confirming an initial metabolic activation of bacterial responses when in the presence of plant root exudates. Moreover, antioxidant genes were mostly expressed during the interaction with the plant exudates. Further evaluation of stress- and methylotrophic-related genes expression by qPCR showed that glutathione peroxidase and glutathione synthetase genes were up-regulated during the Methylobacterium-soybean interaction. These findings support that glutathione (GSH) is potentially a key molecule involved in cellular detoxification during plant root colonization. In addition to methylotrophic metabolism, antioxidant genes, mainly glutathione-related genes, play a key role during soybean exudate recognition and adaptation, the first step in bacterial colonization.201526238382
682120.9986Comparative transcriptome analysis of Brucella melitensis in an acidic environment: Identification of the two-component response regulator involved in the acid resistance and virulence of Brucella. Brucella melitensis, encounters a very stressful environment in phagosomes, especially low pH levels. So identifying the genes that contribute to the replication and survival within an acidic environment is critical in understanding the pathogenesis of the Brucella bacteria. In our research, comparative transcriptome with RNA-seq were used to analyze the changes of genes in normal-medium culture and in pH4.4-medium culture. The results reveal that 113 genes expressed with significant differences (|log2Ratio| ≥ 3); about 44% genes expressed as up-regulated. With GO term analysis, structural constituent of the ribosome, rRNA binding, structural molecule activity, and cation-transporting ATPase activity were significantly enriched (p-value ≤ 0.05). These genes distributed in 51 pathways, in which ribosome and photosynthesis pathways were significantly enriched. Six pathways (oxidative phosphorylation, iron-transporting, bacterial secretion system, transcriptional regulation, two-component system, and ABC transporters pathways) tightly related to the intracellular survival and virulence of Brucella were analyzed. A two-component response regulator gene in the transcriptional regulation pathway, identified through gene deletion and complementary technologies, played an important role in the resistance to the acid-resistance and virulence of Brucella.201626691825
699130.9986DltX of Bacillus thuringiensis Is Essential for D-Alanylation of Teichoic Acids and Resistance to Antimicrobial Response in Insects. The dlt operon of Gram-positive bacteria is required for the incorporation of D-alanine esters into cell wall-associated teichoic acids (TAs). Addition of D-alanine to TAs reduces the negative charge of the cell envelope thereby preventing cationic antimicrobial peptides (CAMPs) from reaching their target of action on the bacterial surface. In most gram-positive bacteria, this operon consists of five genes dltXABCD but the involvement of the first ORF (dltX) encoding a small protein of unknown function, has never been investigated. The aim of this study was to establish whether this protein is involved in the D-alanylation process in Bacillus thuringiensis. We, therefore constructed an in frame deletion mutant of dltX, without affecting the expression of the other genes of the operon. The growth characteristics of the dltX mutant and those of the wild type strain were similar under standard in vitro conditions. However, disruption of dltX drastically impaired the resistance of B. thuringiensis to CAMPs and significantly attenuated its virulence in two insect species. Moreover, high-performance liquid chromatography studies showed that the dltX mutant was devoid of D-alanine, and electrophoretic mobility measurements indicated that the cells carried a higher negative surface charge. Scanning electron microscopy experiments showed morphological alterations of these mutant bacteria, suggesting that depletion of D-alanine from TAs affects cell wall structure. Our findings suggest that DltX is essential for the incorporation of D-alanyl esters into TAs. Therefore, DltX plays a direct role in the resistance to CAMPs, thus contributing to the survival of B. thuringiensis in insects. To our knowledge, this work is the first report examining the involvement of dltX in the D-alanylation of TAs.201728824570
592140.9986Metabolism of Tryptophan and Tryptophan Analogs by Rhizobium meliloti. The alfalfa symbiont Rhizobium meliloti Rm1021 produces indole-3-acetic acid in a regulated manner when supplied with exogenous tryptophan. Mutants with altered response to tryptophan analogs still produce indole-3-acetic acid, but are Fix(-) because bacteria do not fully differentiate into the nitrogen-fixing bacteriod form. These mutations are in apparently essential genes tightly linked to a dominant streptomycin resistance locus.199016667364
8315150.9986The Induction and Modulation of Plant Defense Responses by Bacterial Lipopolysaccharides. Lipopolysaccharides (LPSs) are ubiquitous, indispensable components of the cell surface of Gram-negative bacteria that apparently have diverse roles in bacterial pathogenesis of plants. As an outer membrane component, LPS may contribute to the exclusion of plant-derived antimicrobial compounds promoting the ability of a bacterial plant pathogen to infect plants. In contrast, LPS can be recognized by plants to directly trigger some plant defense-related responses. LPS can also alter the response of plants to subsequent bacterial inoculation; these delayed effects include alterations in the expression patterns of genes coding for some pathogenesis-related (PR) proteins, promotion of the synthesis of antimicrobial hydroxycinnamoyl-tyramine conjugates, and prevention of the hypersensitive reaction caused by avirulent bacteria. Prevention of the response may allow expression of resistance in the absence of catastrophic tissue damage. Recognition of LPS (and other nonspecific determinants) may initiate responses in plants that restrict the growth of nonpathogenic bacteria, whereas plant pathogens may possess hrp gene-dependent mechanisms to suppress such responses.200011701843
8810160.9986Mechanisms involved in the sequestration and resistance of cadmium for a plant-associated Pseudomonas strain. Understanding Cd-resistant bacterial cadmium (Cd) resistance systems is crucial for improving microremediation in Cd-contaminated environments. However, these mechanisms are not fully understood in plant-associated bacteria. In the present study, we investigated the mechanisms underlying Cd sequestration and resistance in the strain AN-B15. These results showed that extracellular Cd sequestration by complexation in strain AN-B15 was primarily responsible for the removal of Cd from the solution. Transcriptome analyses have shown that the mechanisms of Cd resistance at the transcriptional level involve collaborative processes involving multiple metabolic pathways. The AN-B15 strain upregulated the expression of genes related to exopolymeric substance synthesis, metal transport, Fe-S cluster biogenesis, iron recruitment, reactive oxygen species oxidative stress defense, and DNA and protein repair to resist Cd-induced stress. Furthermore, inoculation with AN-B15 alleviated Cd-induced toxicity and reduced Cd uptake in the shoots of wheat seedlings, indicating its potential for remediation. Overall, the results improve our understanding of the mechanisms involved in Cd resistance in bacteria and thus have important implications for improving microremediation.202337806135
8152170.9986Glutathione S-Transferase Enzymes in Plant-Pathogen Interactions. Plant glutathione S-transferases (GSTs) are ubiquitous and multifunctional enzymes encoded by large gene families. A characteristic feature of GST genes is their high inducibility by a wide range of stress conditions including biotic stress. Early studies on the role of GSTs in plant biotic stress showed that certain GST genes are specifically up-regulated by microbial infections. Later numerous transcriptome-wide investigations proved that distinct groups of GSTs are markedly induced in the early phase of bacterial, fungal and viral infections. Proteomic investigations also confirmed the accumulation of multiple GST proteins in infected plants. Furthermore, functional studies revealed that overexpression or silencing of specific GSTs can markedly modify disease symptoms and also pathogen multiplication rates. However, very limited information is available about the exact metabolic functions of disease-induced GST isoenzymes and about their endogenous substrates. The already recognized roles of GSTs are the detoxification of toxic substances by their conjugation with glutathione, the attenuation of oxidative stress and the participation in hormone transport. Some GSTs display glutathione peroxidase activity and these GSTs can detoxify toxic lipid hydroperoxides that accumulate during infections. GSTs can also possess ligandin functions and participate in the intracellular transport of auxins. Notably, the expression of multiple GSTs is massively activated by salicylic acid and some GST enzymes were demonstrated to be receptor proteins of salicylic acid. Furthermore, induction of GST genes or elevated GST activities have often been observed in plants treated with beneficial microbes (bacteria and fungi) that induce a systemic resistance response (ISR) to subsequent pathogen infections. Further research is needed to reveal the exact metabolic functions of GST isoenzymes in infected plants and to understand their contribution to disease resistance.201830622544
8151180.9986Azospirillum: benefits that go far beyond biological nitrogen fixation. The genus Azospirillum comprises plant-growth-promoting bacteria (PGPB), which have been broadly studied. The benefits to plants by inoculation with Azospirillum have been primarily attributed to its capacity to fix atmospheric nitrogen, but also to its capacity to synthesize phytohormones, in particular indole-3-acetic acid. Recently, an increasing number of studies has attributed an important role of Azospirillum in conferring to plants tolerance of abiotic and biotic stresses, which may be mediated by phytohormones acting as signaling molecules. Tolerance of biotic stresses is controlled by mechanisms of induced systemic resistance, mediated by increased levels of phytohormones in the jasmonic acid/ethylene pathway, independent of salicylic acid (SA), whereas in the systemic acquired resistance-a mechanism previously studied with phytopathogens-it is controlled by intermediate levels of SA. Both mechanisms are related to the NPR1 protein, acting as a co-activator in the induction of defense genes. Azospirillum can also promote plant growth by mechanisms of tolerance of abiotic stresses, named as induced systemic tolerance, mediated by antioxidants, osmotic adjustment, production of phytohormones, and defense strategies such as the expression of pathogenesis-related genes. The study of the mechanisms triggered by Azospirillum in plants can help in the search for more-sustainable agricultural practices and possibly reveal the use of PGPB as a major strategy to mitigate the effects of biotic and abiotic stresses on agricultural productivity.201829728787
761190.9986Copper-responsive gene regulation in bacteria. Copper is an essential cofactor of various enzymes, but free copper is highly toxic to living cells. To maintain cellular metabolism at different ambient copper concentrations, bacteria have evolved specific copper homeostasis systems that mostly act as defence mechanisms. As well as under free-living conditions, copper defence is critical for virulence in pathogenic bacteria. Most bacteria synthesize P-type copper export ATPases as principal defence determinants when copper concentrations exceed favourable levels. In addition, many bacteria utilize resistance-nodulation-cell division (RND)-type efflux systems and multicopper oxidases to cope with excess copper. This review summarizes our current knowledge on copper-sensing transcriptional regulators, which we assign to nine different classes. Widespread one-component regulators are CueR, CopY and CsoR, which were initially identified in Escherichia coli, Enterococcus hirae and Mycobacterium tuberculosis, respectively. CueR activates homeostasis gene expression at elevated copper concentrations, while CopY and CsoR repress their target genes under copper-limiting conditions. Besides these one-component systems, which sense the cytoplasmic copper status, many Gram-negative bacteria utilize two-component systems, which sense periplasmic copper concentrations. In addition to these well-studied transcriptional factors, copper control mechanisms acting at the post-transcriptional and the post-translational levels will be discussed.201222918892