A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics
TL;DR: The results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.
About: This article is published in Cell.The article was published on 2007-09-07 and is currently open access. It has received 2420 citations till now. The article focuses on the topics: Hydroxyl radical & DNA damage.
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TL;DR: A review of antibiotic resistance development over the past half-century can be found in this article, with the oft-restated conclusion that it is time to act and to restore the therapeutic applications of antibiotics.
Abstract: Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.
4,364 citations
TL;DR: The multilayered effects of drug–target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing are discussed.
Abstract: Antibiotic drug-target interactions, and their respective direct effects, are generally well characterized. By contrast, the bacterial responses to antibiotic drug treatments that contribute to cell death are not as well understood and have proven to be complex as they involve many genetic and biochemical pathways. In this Review, we discuss the multilayered effects of drug-target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing. We also discuss new insights into these mechanisms that have been revealed through the study of biological networks, and describe how these insights, together with related developments in synthetic biology, could be exploited to create new antibacterial therapies.
1,796 citations
Cites background from "A Common Mechanism of Cellular Deat..."
...In addition, recent evidence points towards a common mechanism of cell death involving disadvantageous cell responses to drug-induced stresses that are shared by all classes of bactericidal antibiotics, which ultimately contributes to killing by these drug...
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TL;DR: The different roles of iron in triggering cell death, targets of iron-dependent ROS that mediate cell death and a new form ofIron-dependent cell death termed ferroptosis are described to suggest new therapeutic avenues to treat cancer, organ damage and degenerative disease.
Abstract: The transition metal iron is essential for life, yet potentially toxic iron-catalyzed reactive oxygen species (ROS) are unavoidable in an oxygen-rich environment. Iron and ROS are increasingly recognized as important initiators and mediators of cell death in a variety of organisms and pathological situations. Here, we review recent discoveries regarding the mechanism by which iron and ROS participate in cell death. We describe the different roles of iron in triggering cell death, targets of iron-dependent ROS that mediate cell death and a new form of iron-dependent cell death termed ferroptosis. Recent advances in understanding the role of iron and ROS in cell death offer unexpected surprises and suggest new therapeutic avenues to treat cancer, organ damage and degenerative disease.
1,491 citations
TL;DR: The biology of latent tuberculosis is discussed as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria.
Abstract: Immunological tests provide evidence of latent tuberculosis in one third of the global population, which corresponds to more than two billion individuals. Latent tuberculosis is defined by the absence of clinical symptoms but carries a risk of subsequent progression to clinical disease, particularly in the context of co-infection with HIV. In this Review we discuss the biology of latent tuberculosis as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria. We then show how this model can be used to develop a rational programme to discover effective drugs for the eradication of M. tuberculosis infection.
1,254 citations
TL;DR: The de novo engineering of genetic circuits, biological modules and synthetic pathways is beginning to address these crucial problems and is being used in related practical applications.
Abstract: Synthetic biology is bringing together engineers and biologists to design and build novel biomolecular components, networks and pathways, and to use these constructs to rewire and reprogram organisms. These re-engineered organisms will change our lives over the coming years, leading to cheaper drugs, 'green' means to fuel our cars and targeted therapies for attacking 'superbugs' and diseases, such as cancer. The de novo engineering of genetic circuits, biological modules and synthetic pathways is beginning to address these crucial problems and is being used in related practical applications.
1,247 citations
References
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TL;DR: The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing.
Abstract: Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
35,225 citations
"A Common Mechanism of Cellular Deat..." refers methods in this paper
...For additional pathway-level insights, we performed Gene Ontology-based enrichment (Ashburner et al., 2000; Camon et al., 2004) of the up- and downregulated gene lists using GO::TermFinder (Boyle et al., 2004), requiring pathway enrichment q values to be <0.05 and setting the p value estimation mode to bootstrapping....
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...Continued Gene Function ypeA putative acetyltransferase yraQ predicted permease yrhB hypothetical protein ytfA predicted transcriptional regulator a Pathway enrichment using Gene Ontology identified NADHcoupled electron transport (false discovery rate = 0.0345) as the only upregulated pathway common to all three bactericidal drug classes....
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...Interestingly, pathway enrichment (q value < 0.05) using Gene Ontology (Ashburner et al., 2000; Camon et al., 2004) found NADH-coupled electron transport (NADH dehydrogenase I) to be a key upregulated pathway common to all three bactericidal drug classes (Table 1)....
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...For additional pathway-level insights, we performed Gene Ontology-based enrichment (Ashburner et al., 2000; Camon et al., 2004) of the up- and downregulated gene lists using GO::TermFinder (Boyle et al., 2004), requiring pathway enrichment q values to be <0.05 and setting the p value estimation…...
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...For additional pathway-level insights, we performed Gene Ontology-based enrichment (Ashburner et al., 2000; Camon et al., 2004) of the up- and downregulated gene lists using GO::TermFinder (Boyle et al....
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TL;DR: A simple and highly efficient method to disrupt chromosomal genes in Escherichia coli in which PCR primers provide the homology to the targeted gene(s), which should be widely useful, especially in genome analysis of E. coli and other bacteria.
Abstract: We have developed a simple and highly efficient method to disrupt chromosomal genes in Escherichia coli in which PCR primers provide the homology to the targeted gene(s). In this procedure, recombination requires the phage lambda Red recombinase, which is synthesized under the control of an inducible promoter on an easily curable, low copy number plasmid. To demonstrate the utility of this approach, we generated PCR products by using primers with 36- to 50-nt extensions that are homologous to regions adjacent to the gene to be inactivated and template plasmids carrying antibiotic resistance genes that are flanked by FRT (FLP recognition target) sites. By using the respective PCR products, we made 13 different disruptions of chromosomal genes. Mutants of the arcB, cyaA, lacZYA, ompR-envZ, phnR, pstB, pstCA, pstS, pstSCAB-phoU, recA, and torSTRCAD genes or operons were isolated as antibiotic-resistant colonies after the introduction into bacteria carrying a Red expression plasmid of synthetic (PCR-generated) DNA. The resistance genes were then eliminated by using a helper plasmid encoding the FLP recombinase which is also easily curable. This procedure should be widely useful, especially in genome analysis of E. coli and other bacteria because the procedure can be done in wild-type cells.
14,389 citations
"A Common Mechanism of Cellular Deat..." refers methods in this paper
...Removal of the kanamycin-resistance cassette was accomplished using the pcp20 plasmid (Datsenko and Wanner, 2000) (Table S4) and confirmed by PCR prior to experimentation....
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...Positive P1 transductants were confirmed by acquisition of kanamycin resistance and PCR. Removal of the kanamycin-resistance cassette was accomplished using the pcp20 plasmid (Datsenko and Wanner, 2000) (Table S4) and confirmed by PCR prior to experimentation....
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TL;DR: This work proposes an approach to measuring statistical significance in genomewide studies based on the concept of the false discovery rate, which offers a sensible balance between the number of true and false positives that is automatically calibrated and easily interpreted.
Abstract: With the increase in genomewide experiments and the sequencing of multiple genomes, the analysis of large data sets has become commonplace in biology. It is often the case that thousands of features in a genomewide data set are tested against some null hypothesis, where a number of features are expected to be significant. Here we propose an approach to measuring statistical significance in these genomewide studies based on the concept of the false discovery rate. This approach offers a sensible balance between the number of true and false positives that is automatically calibrated and easily interpreted. In doing so, a measure of statistical significance called the q value is associated with each tested feature. The q value is similar to the well known p value, except it is a measure of significance in terms of the false discovery rate rather than the false positive rate. Our approach avoids a flood of false positive results, while offering a more liberal criterion than what has been used in genome scans for linkage.
9,239 citations
"A Common Mechanism of Cellular Deat..." refers methods in this paper
...For each time point in each bactericidal experiment set (norfloxacin, ampicillin, and kanamycin), we converted Dz scores to p values and chose significantly up- and downregulated genes by selecting those with a q value 0.05 (false discovery rate) (Storey and Tibshirani, 2003)....
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TL;DR: Three methods of performing normalization at the probe intensity level are presented: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure and the simplest and quickest complete data method is found to perform favorably.
Abstract: Motivation: When running experiments that involve multiple high density oligonucleotide arrays, it is important to remove sources of variation between arrays of non-biological origin. Normalization is a process for reducing this variation. It is common to see non-linear relations between arrays and the standard normalization provided by Affymetrix does not perform well in these situations. Results: We present three methods of performing normalization at the probe intensity level. These methods are called complete data methods because they make use of data from all arrays in an experiment to form the normalizing relation. These algorithms are compared to two methods that make use of a baseline array: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure. Two publicly available datasets are used to carry out the comparisons. The simplest and quickest complete data method is found to perform favorably. Availabilty: Software implementing all three of the complete data normalization methods is available as part of the R package Affy, which is a part of the Bioconductor project http://www.bioconductor.org. Contact: bolstad@stat.berkeley.edu Supplementary information: Additional figures may be found at http://www.stat.berkeley.edu/∼bolstad/normalize/ index.html
8,324 citations
"A Common Mechanism of Cellular Deat..." refers methods in this paper
...The resulting microarray *.CEL files were combined with *.CEL files from arrays that comprise the M3D compendium (Faith et al., 2007) (http://m3d.bu.edu; E_coli_v3_Build_3) and RMA normalized (Bolstad et al., 2003) with RMAExpress, for a total of 524 RMA-normalized E. coli expression arrays....
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...edu; E_coli_v3_Build_3) and RMA normalized (Bolstad et al., 2003) with RMAExpress, for a total of 524 RMA-normalized E....
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TL;DR: These mutants—the ‘Keio collection’—provide a new resource not only for systematic analyses of unknown gene functions and gene regulatory networks but also for genome‐wide testing of mutational effects in a common strain background, E. coli K‐12 BW25113.
Abstract: We have systematically made a set of precisely defined, single-gene deletions of all nonessential genes in Escherichia coli K-12. Open-reading frame coding regions were replaced with a kanamycin cassette flanked by FLP recognition target sites by using a one-step method for inactivation of chromosomal genes and primers designed to create in-frame deletions upon excision of the resistance cassette. Of 4288 genes targeted, mutants were obtained for 3985. To alleviate problems encountered in high-throughput studies, two independent mutants were saved for every deleted gene. These mutants-the 'Keio collection'-provide a new resource not only for systematic analyses of unknown gene functions and gene regulatory networks but also for genome-wide testing of mutational effects in a common strain background, E. coli K-12 BW25113. We were unable to disrupt 303 genes, including 37 of unknown function, which are candidates for essential genes. Distribution is being handled via GenoBase (http://ecoli.aist-nara.ac.jp/).
7,428 citations
"A Common Mechanism of Cellular Deat..." refers methods in this paper
...The recA, iscS, and TCA-cycle knockouts were constructed using P1 phage transduction and were derived from an E. coli single-gene knockout library (Baba et al., 2006) (Table S4)....
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