In search of the missing ligands for TetR family regulators. - Related Documents




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75601.0000In search of the missing ligands for TetR family regulators. The TetR family of microbial transcription factors directly control the expression of a diverse range of genes in bacteria by sensing specific ligands. In this issue of Chemistry & and Biology, Cuthbertson and colleagues used phylogenomics to guide the identification of TetR-like protein cognate ligands and revealed a novel inducible antibiotic resistance mechanism.201323438741
76210.9996MerR family transcription activators: similar designs, different specificities. Living organisms use metals for a variety of essential functions, and face the problems of how to acquire and regulate the intracellular levels of those metals they need, differentiate between essential and toxic metals, and remove from the cell or detoxify metals that are toxic. In bacteria, cytoplasmic metal ion responsive transcriptional regulators are important in regulating the expression of genes involved in metal ion homeostasis and efflux systems. The MerR family of transcriptional activators are metal sensing regulators that are found in different bacteria and have a common design, but have evolved to recognize and respond to different metals. In this issue of Molecular Microbiology, work by Checa and colleagues describes for the first time a gold-specific MerR family regulator named GolS from Salmonella enterica serovar Typhimurium that controls the production of an efflux pump and a metal chaperone protein that confer resistance to Au salts.200717302809
831220.9996MarA, SoxS and Rob of Escherichia coli - Global regulators of multidrug resistance, virulence and stress response. Bacteria have a great capacity for adjusting their metabolism in response to environmental changes by linking extracellular stimuli to the regulation of genes by transcription factors. By working in a co-operative manner, transcription factors provide a rapid response to external threats, allowing the bacteria to survive. This review will focus on transcription factors MarA, SoxS and Rob in Escherichia coli, three members of the AraC family of proteins. These homologous proteins exemplify the ability to respond to multiple threats such as oxidative stress, drugs and toxic compounds, acidic pH, and host antimicrobial peptides. MarA, SoxS and Rob recognize similar DNA sequences in the promoter region of more than 40 regulatory target genes. As their regulons overlap, a finely tuned adaptive response allows E. coli to survive in the presence of different assaults in a co-ordinated manner. These regulators are well conserved amongst Enterobacteriaceae and due to their broad involvement in bacterial adaptation in the host, have recently been explored as targets to develop new anti-virulence agents. The regulators are also being examined for their roles in novel technologies such as biofuel production.201324860636
29330.9996Gene regulation by tetracyclines. Constraints of resistance regulation in bacteria shape TetR for application in eukaryotes. The Tet repressor protein (TetR) regulates transcription of a family of tetracycline (tc) resistance determinants in Gram-negative bacteria. The resistance protein TetA, a membrane-spanning H+-[tc.M]+ antiporter, must be sensitively regulated because its expression is harmful in the absence of tc, yet it has to be expressed before the drugs' concentration reaches cytoplasmic levels inhibitory for protein synthesis. Consequently, TetR shows highly specific tetO binding to reduce basal expression and high affinity to tc to ensure sensitive induction. Tc can cross biological membranes by diffusion enabling this inducer to penetrate the majority of cells. These regulatory and pharmacological properties are the basis for application of TetR to selectively control the expression of single genes in lower and higher eukaryotes. TetR can be used for that purpose in some organisms without further modifications. In mammals and in a large variety of other organisms, however, eukaryotic transcriptional activator or repressor domains are fused to TetR to turn it into an efficient regulator. Mechanistic understanding and the ability to engineer and screen for mutants with specific properties allow tailoring of the DNA recognition specificity, the response to inducer tc and the dimerization specificity of TetR-based eukaryotic regulators. This review provides an overview of the TetR properties as they evolved in bacteria, the functional modifications necessary to transform it into a convenient, specific and efficient regulator for use in eukaryotes and how the interplay between structure--function studies in bacteria and specific requirements of particular applications in eukaryotes have made it a versatile and highly adaptable regulatory system.200312869186
833240.9996The bacterial LexA transcriptional repressor. Bacteria respond to DNA damage by mounting a coordinated cellular response, governed by the RecA and LexA proteins. In Escherichia coli, RecA stimulates cleavage of the LexA repressor, inducing more than 40 genes that comprise the SOS global regulatory network. The SOS response is widespread among bacteria and exhibits considerable variation in its composition and regulation. In some well-characterised pathogens, induction of the SOS response modulates the evolution and dissemination of drug resistance, as well as synthesis, secretion and dissemination of the virulence. In this review, we discuss the structure of LexA protein, particularly with respect to distinct conformations that enable repression of SOS genes via specific DNA binding or repressor cleavage during the response to DNA damage. These may provide new starting points in the battle against the emergence of bacterial pathogens and the spread of drug resistance among them.200918726173
75850.9995Term-seq reveals abundant ribo-regulation of antibiotics resistance in bacteria. Riboswitches and attenuators are cis-regulatory RNA elements, most of which control bacterial gene expression via metabolite-mediated, premature transcription termination. We developed an unbiased experimental approach for genome-wide discovery of such ribo-regulators in bacteria. We also devised an experimental platform that quantitatively measures the in vivo activity of all such regulators in parallel and enables rapid screening for ribo-regulators that respond to metabolites of choice. Using this approach, we detected numerous antibiotic-responsive ribo-regulators that control antibiotic resistance genes in pathogens and in the human microbiome. Studying one such regulator in Listeria monocytogenes revealed an attenuation mechanism mediated by antibiotic-stalled ribosomes. Our results expose broad roles for conditional termination in regulating antibiotic resistance and provide a tool for discovering riboswitches and attenuators that respond to previously unknown ligands.201627120414
77160.9995The multiple antibiotic resistance operon of enteric bacteria controls DNA repair and outer membrane integrity. The multiple antibiotic resistance (mar) operon of Escherichia coli is a paradigm for chromosomally encoded antibiotic resistance in enteric bacteria. The locus is recognised for its ability to modulate efflux pump and porin expression via two encoded transcription factors, MarR and MarA. Here we map binding of these regulators across the E. coli genome and identify an extensive mar regulon. Most notably, MarA activates expression of genes required for DNA repair and lipid trafficking. Consequently, the mar locus reduces quinolone-induced DNA damage and the ability of tetracyclines to traverse the outer membrane. These previously unrecognised mar pathways reside within a core regulon, shared by most enteric bacteria. Hence, we provide a framework for understanding multidrug resistance, mediated by analogous systems, across the Enterobacteriaceae. Transcription factors MarR and MarA confer multidrug resistance in enteric bacteria by modulating efflux pump and porin expression. Here, Sharma et al. show that MarA also upregulates genes required for lipid trafficking and DNA repair, thus reducing antibiotic entry and quinolone-induced DNA damage.201729133912
888470.9995Regulatory Mechanisms of the LuxS/AI-2 System and Bacterial Resistance. The quorum-sensing (QS) system is an intercellular cell-cell communication mechanism that controls the expression of genes involved in a variety of cellular processes and that plays critical roles in the adaption and survival of bacteria in their environment. The LuxS/AI-2 QS system, which uses AI-2 (autoinducer-2) as a signal molecule, has been identified in both Gram-negative and Gram-positive bacteria. As one of the important global regulatory networks in bacteria, it responds to fluctuations in the numbers of bacteria and regulates the expression of a number of genes, thus affecting cell behavior. We summarize here the known relationships between the LuxS/AI-2 system and drug resistance, discuss the inhibition of LuxS/AI-2 system as an approach to prevent bacterial resistance, and present new strategies for the treatment of drug-resistant pathogens.201931383657
29480.9995Status quo of tet regulation in bacteria. The tetracycline repressor (TetR) belongs to the most popular, versatile and efficient transcriptional regulators used in bacterial genetics. In the tetracycline (Tc) resistance determinant tet(B) of transposon Tn10, tetR regulates the expression of a divergently oriented tetA gene that encodes a Tc antiporter. These components of Tn10 and of other natural or synthetic origins have been used for tetracycline-dependent gene regulation (tet regulation) in at least 40 bacterial genera. Tet regulation serves several purposes such as conditional complementation, depletion of essential genes, modulation of artificial genetic networks, protein overexpression or the control of gene expression within cell culture or animal infection models. Adaptations of the promoters employed have increased tet regulation efficiency and have made this system accessible to taxonomically distant bacteria. Variations of TetR, different effector molecules and mutated DNA binding sites have enabled new modes of gene expression control. This article provides a current overview of tet regulation in bacteria.202234713957
890290.9995RecA Inhibitors Potentiate Antibiotic Activity and Block Evolution of Antibiotic Resistance. Antibiotic resistance arises from the maintenance of resistance mutations or genes acquired from the acquisition of adaptive de novo mutations or the transfer of resistance genes. Antibiotic resistance is acquired in response to antibiotic therapy by activating SOS-mediated DNA repair and mutagenesis and horizontal gene transfer pathways. Initiation of the SOS pathway promotes activation of RecA, inactivation of LexA repressor, and induction of SOS genes. Here, we have identified and characterized phthalocyanine tetrasulfonic acid RecA inhibitors that block antibiotic-induced activation of the SOS response. These inhibitors potentiate the activity of bactericidal antibiotics, including members of the quinolone, β-lactam, and aminoglycoside families in both Gram-negative and Gram-positive bacteria. They reduce the ability of bacteria to acquire antibiotic resistance mutations and to transfer mobile genetic elements conferring resistance. This study highlights the advantage of including RecA inhibitors in bactericidal antibiotic therapies and provides a new strategy for prolonging antibiotic shelf life.201626991103
8280100.9995Regulation of the Expression of Bacterial Multidrug Exporters by Two-Component Signal Transduction Systems. Bacterial multidrug exporters confer resistance to a wide range of antibiotics, dyes, and biocides. Recent studies have shown that there are many multidrug exporters encoded in bacterial genome. For example, it was experimentally identified that E. coli has at least 20 multidrug exporters. Because many of these multidrug exporters have overlapping substrate spectra, it is intriguing that bacteria, with their economically organized genomes, harbor such large sets of multidrug exporter genes. The key to understanding how bacteria utilize these multiple exporters lies in the regulation of exporter expression. Bacteria have developed signaling systems for eliciting a variety of adaptive responses to their environments. These adaptive responses are often mediated by two-component regulatory systems. In this chapter, the method to identify response regulators that affect expression of multidrug exporters is described.201829177834
764110.9995Fungal ATP-binding cassette (ABC) transporters in drug resistance & detoxification. Pleiotropic drug resistance (PDR) is a well-described phenomenon occurring in fungi. PDR shares several similarities with processes in bacteria and higher eukaryotes. In mammalian cells, multidrug resistance (MDR) develops from an initial single drug resistance, eventually leading to a broad cross-resistance to many structurally and functionally unrelated compounds. Notably, a number of membrane-embedded energy-consuming ATP-binding cassette (ABC) transporters have been implicated in the development of PDR/MDR phenotypes. The yeast Saccharomyces cerevisiae genome harbors some 30 genes encoding ABC proteins, several of which mediate PDR. Therefore, yeast served as an important model organism to study the functions of evolutionary conserved ABC genes, including those mediating clinical antifungal resistance in fungal pathogens. Moreover, yeast cells lacking endogenous ABC pumps are hypersensitive to many antifungal drugs, making them suitable for functional studies and cloning of ABC transporters from fungal pathogens such as Candida albicans. This review discusses drug resistance phenomena mediated by ABC transporters in the model system S. cerevisiae and certain fungal pathogens.200616611035
757120.9995Regulation of antibiotic-resistance by non-coding RNAs in bacteria. Antibiotic resistance genes are commonly regulated by sophisticated mechanisms that activate gene expression in response to antibiotic exposure. Growing evidence suggest that cis-acting non-coding RNAs play a major role in regulating the expression of many resistance genes, specifically those which counteract the effects of translation-inhibiting antibiotics. These ncRNAs reside in the 5'UTR of the regulated gene, and sense the presence of the antibiotics by recruiting translating ribosomes onto short upstream open reading frames (uORFs) embedded in the ncRNA. In the presence of translation-inhibiting antibiotics ribosomes arrest over the uORF, altering the RNA structure of the regulator and switching the expression of the resistance gene to 'ON'. The specificity of these riboregulators is tuned to sense-specific classes of antibiotics based on the length and composition of the respective uORF. Here we review recent work describing new types of antibiotic-sensing RNA-based regulators and elucidating the molecular mechanisms by which they function to control antibiotic resistance in bacteria.201728414973
9357130.9994The bifunctional enzymes of antibiotic resistance. The evolutionary union of two genes--each encoding proteins of complementary enzymatic activity--into a single gene so as to allow the coordinated expression of these activities as a fusion polypeptide, is an increasingly recognized biological occurrence. The result of this genetic union is the bifunctional enzyme. This fusion of separate catalytic activities into a single protein, whose gene is regulated by a single promoter, is seen especially where the coordinated expression of the separate activities is highly desirable. Increasingly, a circumstance driving the evolution of the bifunctional enzyme in bacteria is the resistance response of bacteria to antibiotic chemotherapy. We summarize the knowledge on bifunctional antibiotic-resistance enzymes, as possible harbingers of clinically significant resistance mechanisms of the future.200919615931
9356140.9994The expression of antibiotic resistance genes in antibiotic-producing bacteria. Antibiotic-producing bacteria encode antibiotic resistance genes that protect them from the biologically active molecules that they produce. The expression of these genes needs to occur in a timely manner: either in advance of or concomitantly with biosynthesis. It appears that there have been at least two general solutions to this problem. In many cases, the expression of resistance genes is tightly linked to that of antibiotic biosynthetic genes. In others, the resistance genes can be induced by their cognate antibiotics or by intermediate molecules from their biosynthetic pathways. The regulatory mechanisms that couple resistance to antibiotic biosynthesis are mechanistically diverse and potentially relevant to the origins of clinical antibiotic resistance.201424964724
9198150.9994Recognition of bacterial avirulence proteins occurs inside the plant cell: a general phenomenon in resistance to bacterial diseases? One of the recent exciting developments in the research area of plant-microbe interactions is a breakthrough in understanding part of the initial signalling between avirulent Gram-negative bacteria and resistant plants. For resistance to occur, both interacting organisms need to express matching genes, the plant resistance gene and the bacterial avirulence gene. The biochemical function of bacterial avirulence genes and the nature of the signal molecules recognized by the plant have been a mystery for a long time. Recently, several laboratories have shown that bacterial avirulence proteins function as elicitors that are perceived within the plant cell.19979263447
755160.9994Pervasive gene deregulation underlies adaptation and maladaptation in trimethoprim-resistant E. coli. Bacteria employ a number of mechanisms to adapt to antibiotics. Mutations in transcriptional regulators alter the expression levels of genes that can change the susceptibility of bacteria to antibiotics. Two-component signaling proteins are a major class of signaling molecule used by bacteria to regulate transcription. In previous work, we found that mutations in MgrB, a feedback regulator of the PhoQP two-component system, conferred trimethoprim tolerance to Escherichia coli. Here, we elucidate how mutations in MgrB have a domino-like effect on the gene regulatory network of E. coli. As a result, pervasive perturbation of gene regulation ensues. Depending on the environmental context, this pervasive deregulation is either adaptive or maladaptive. Our study sheds light on how deregulation of gene expression can be beneficial for bacteria when challenged with antibiotics, and why regulators like MgrB may have evolved in the first place.202338032208
9165170.9994Regulatory Mechanisms and Physiological Impacts of Quorum Sensing in Gram-Negative Bacteria. The Quorum sensing (QS) system is a widely existing communication mechanism, which regulates bacterial community behaviors and the expression of specific genes. The most common pathogenic bacteria in clinical infections are gram-negative bacteria, and QS plays an important regulatory role in the production of virulence factors and development of antibiotic resistance. This article reviews the QS systems of gram-negative bacteria and provides an overview of how they regulate their physiological functions.202439654694
291180.9994Deregulation of translation due to post-transcriptional modification of rRNA explains why erm genes are inducible. A key mechanism of bacterial resistance to macrolide antibiotics is the dimethylation of a nucleotide in the large ribosomal subunit by erythromycin resistance methyltransferases. The majority of erm genes are expressed only when the antibiotic is present and the erythromycin resistance methyltransferase activity is critical for the survival of bacteria. Although these genes were among the first discovered inducible resistance genes, the molecular basis for their inducibility has remained unknown. Here we show that erythromycin resistance methyltransferase expression reduces cell fitness. Modification of the nucleotide in the ribosomal tunnel skews the cellular proteome by deregulating the expression of a set of proteins. We further demonstrate that aberrant translation of specific proteins results from abnormal interactions of the nascent peptide with the erythromycin resistance methyltransferase-modified ribosomal tunnel. Our findings provide a plausible explanation why erm genes have evolved to be inducible and underscore the importance of nascent peptide recognition by the ribosome for generating a balanced cellular proteome.201323749080
8215190.9994Insight into Two ABC Transporter Families Involved in Lantibiotic Resistance. Antimicrobial peptides, which contain (methyl)-lanthionine-rings are called lantibiotics. They are produced by several Gram-positive bacteria and are mainly active against these bacteria. Although these are highly potent antimicrobials, some human pathogenic bacteria express specific ABC transporters that confer resistance and counteract their antimicrobial activity. Two distinct ABC transporter families are known to be involved in this process. These are the Cpr- and Bce-type ABC transporter families, named after their involvement in cationic peptide resistance in Clostridium difficile, and bacitracin efflux in Bacillus subtilis, respectively. Both resistance systems differentiate to each other in terms of the proteins involved. Here, we summarize the current knowledge and describe the divergence as well as the common features present in both the systems to confer lantibiotic resistance.201729404338