# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 9696 | 0 | 0.9999 | Evolution of resistance in microorganisms of human origin. Resistance to antimicrobials in bacteria results from either evolution of "new" DNA or from variation in existing DNA. Evidence suggests that new DNA did not originate since the use of antibiotics in medicine, but evolved long ago in soil bacteria. This evidence is based on functional and structural homologies of resistance proteins in human pathogens, and resistance proteins or physiological proteins of soil bacteria. Variation in existing DNA has been shown to comprise variations in structural or regulatory genes of the normal chromosome or mutations in already existing plasmid-mediated resistance genes modifying the resistance phenotype. The success of R-determinants in human pathogens was due to their horizontal spread by transformation, transduction and conjugation. Furthermore, transposition has enabled bacteria to efficiently distribute R-determinants between independent DNA-molecules. Since the genetic processes involved in the development of resistance are rare events, the selective pressure exerted by antibiotics has significantly contributed to the overall evolutionary picture. With few exceptions, experimental data about the role of antibiotic usage outside human medicine with respect to the resistance problem in human pathogens are missing. Epidemiological data about the occurrence of resistance in human pathogens seem to indicate that the major contributing factor to the problem we face today was the extensive use of antibiotics in medicine itself. | 1993 | 8212510 |
| 9434 | 1 | 0.9999 | Facilitation of horizontal transfer of antimicrobial resistance by transformation of antibiotic-induced cell-wall-deficient bacteria. It is universally accepted that the use of antibiotics will lead to antimicrobial resistance. Traditionally, the explanation to this phenomenon was random mutation and horizontal gene transfer and amplification by selective pressure. Subsequently, a second mechanism of antibiotic-induced antimicrobial resistance acquisition was proposed, when Davies et al. discovered that genes encoding antimicrobial resistance are present in bacteria that produce antibiotics, and during the process of antibiotic purification from these antibiotic-producing organisms, remnants of the organisms' DNA that contain antibiotic resistance genes are also co-extracted, and can be recovered in antibiotic preparations. In addition to selective pressure and antimicrobial resistance genes in antibiotic preparations, we hypothesize the third mechanism by which administration of antibiotics leads to antimicrobial resistance. beta-Lactams and glycopeptides damage bacteria by inhibiting cell wall murein synthesis. During the process, cell-wall-deficient forms are generated before the bacteria die. These cell-wall-deficient forms have an increased ability to uptake DNA by transformation. It has been demonstrated that plasmids encoding antimicrobial resistance of Staphylococcus aureus can be transformed to Bacillus subtilis after the B. subtilis was treated with penicillin or lysostaphin, a chemical that damage the cell walls of some Gram-positive bacteria; and that short treatment of Escherichia coli with antibiotics disturbing bacterial cell wall synthesis rendered the cells capable of absorbing foreign DNA. Since bacteria occupying the same ecological niche, such as the lower gastrointestinal tract, is common, bacteria are often incubated with foreign DNA encoding resistance coming from the administration of antibiotics or other bacteria that undergone lysis unrelated to antibiotic-induced killing. As few as a single antibiotic resistant gene is taken up by the cell-wall-deficient form, it will develop into a resistant clone, despite most of the other bacteria are killed by the antibiotic. If the hypothesis is correct, one should reduce the use of antibiotics that perturb bacterial cell wall synthesis, such as beta-lactams, which is the largest group being manufactured, in both humans and animals, in order to reduce the acquisition of antibiotic resistance through this mechanism. In contrast to the old theory that antibiotics only provide selective pressures for the development of antimicrobial resistance, antibiotics by themselves are able to generate the whole chain of events towards the development of antimicrobial resistance. Antibiotics provide a source of antimicrobial resistance genes, facilitate the horizontal transfer of antimicrobial resistance genes through facilitating transformation, and provide selective pressures for amplification of the antimicrobial resistance genes. That is perhaps an important reason why antimicrobial resistance is so difficult to control. Further experiments should be performed to delineate which particular type of beta-lactam antibiotics are associated with increase in transformation efficiencies more than the others, so that we can select those less resistance generating beta-lactam for routine usage. | 2003 | 13679020 |
| 9406 | 2 | 0.9999 | Proteomics as the final step in the functional metagenomics study of antimicrobial resistance. The majority of clinically applied antimicrobial agents are derived from natural products generated by soil microorganisms and therefore resistance is likely to be ubiquitous in such environments. This is supported by the fact that numerous clinically important resistance mechanisms are encoded within the genomes of such bacteria. Advances in genomic sequencing have enabled the in silico identification of putative resistance genes present in these microorganisms. However, it is not sufficient to rely on the identification of putative resistance genes, we must also determine if the resultant proteins confer a resistant phenotype. This will require an analysis pipeline that extends from the extraction of environmental DNA, to the identification and analysis of potential resistance genes and their resultant proteins and phenotypes. This review focuses on the application of functional metagenomics and proteomics to study antimicrobial resistance in diverse environments. | 2015 | 25784907 |
| 9289 | 3 | 0.9999 | Artificial Gene Amplification in Escherichia coli Reveals Numerous Determinants for Resistance to Metal Toxicity. When organisms are subjected to environmental challenges, including growth inhibitors and toxins, evolution often selects for the duplication of endogenous genes, whose overexpression can provide a selective advantage. Such events occur both in natural environments and in clinical settings. Microbial cells-with their large populations and short generation times-frequently evolve resistance to a range of antimicrobials. While microbial resistance to antibiotic drugs is well documented, less attention has been given to the genetic elements responsible for resistance to metal toxicity. To assess which overexpressed genes can endow gram-negative bacteria with resistance to metal toxicity, we transformed a collection of plasmids overexpressing all E. coli open reading frames (ORFs) into naive cells, and selected for survival in toxic concentrations of six transition metals: Cd, Co, Cu, Ni, Ag, Zn. These selections identified 48 hits. In each of these hits, the overexpression of an endogenous E. coli gene provided a selective advantage in the presence of at least one of the toxic metals. Surprisingly, the majority of these cases (28/48) were not previously known to function in metal resistance or homeostasis. These findings highlight the diverse mechanisms that biological systems can deploy to adapt to environments containing toxic concentrations of metals. | 2018 | 29356848 |
| 9269 | 4 | 0.9999 | The Stringent Response Promotes Antibiotic Resistance Dissemination by Regulating Integron Integrase Expression in Biofilms. Class 1 integrons are genetic systems that enable bacteria to capture and express gene cassettes. These integrons, when isolated in clinical contexts, most often carry antibiotic resistance gene cassettes. They play a major role in the dissemination of antibiotic resistance among Gram-negative bacteria. The key element of integrons is the integrase, which allows gene cassettes to be acquired and shuffled. Planktonic culture experiments have shown that integrase expression is regulated by the bacterial SOS response. In natural settings, however, bacteria generally live in biofilms, which are characterized by strong antibiotic resilience and by increased expression of stress-related genes. Here, we report that under biofilm conditions, the stringent response, which is induced upon starvation, (i) increases basal integrase and SOS regulon gene expression via induction of the SOS response and (ii) exerts biofilm-specific regulation of the integrase via the Lon protease. This indicates that biofilm environments favor integron-mediated acquisition of antibiotic resistance and other adaptive functions encoded by gene cassettes. IMPORTANCE: Multidrug-resistant bacteria are becoming a worldwide health problem. Integrons are bacterial genetic platforms that allow the bacteria to capture and express gene cassettes. In clinical settings, integrons play a major role in the dissemination of antibiotic resistance gene cassettes among Gram-negative bacteria. Cassette capture is catalyzed by the integron integrase, whose expression is induced by DNA damage and controlled by the bacterial SOS response in laboratory planktonic cultures. In natural settings, bacteria usually grow in heterogeneous environments known as biofilms, which have very different conditions than planktonic cultures. Integrase regulation has not been investigated in biofilms. Our results showed that in addition to the SOS response, the stringent response (induced upon starvation) is specifically involved in the regulation of class 1 integron integrases in biofilms. This study shows that biofilms are favorable environments for integron-mediated acquisition/exchange of antibiotic resistance genes by bacteria and for the emergence of multidrug-resistant bacteria. | 2016 | 27531906 |
| 9288 | 5 | 0.9999 | Understanding cellular responses to toxic agents: a model for mechanism-choice in bacterial metal resistance. Bacterial resistances to metals are heterogeneous in both their genetic and biochemical bases. Metal resistance may be chromosomally-, plasmid- or transposon-encoded, and one or more genes may be involved: at the biochemical level at least six different mechanisms are responsible for resistance. Various types of resistance mechanisms can occur singly or in combination and for a particular metal different mechanisms of resistance can occur in the same species. To understand better the diverse responses of bacteria to metal ion challenge we have constructed a qualitative model for the selection of metal resistance in bacteria. How a bacterium becomes resistant to a particular metal depends on the number and location of cellular components sensitive to the specific metal ion. Other important selective factors include the nature of the uptake systems for the metal, the role and interactions of the metal in the normal metabolism of the cell and the availability of plasmid (or transposon) encoded resistance mechanisms. The selection model presented is based on the interaction of these factors and allows predictions to be made about the evolution of metal resistance in bacterial populations. It also allows prediction of the genetic basis and of mechanisms of resistance which are in substantial agreement with those in well-documented populations. The interaction of, and selection for resistance to, toxic substances in addition to metals, such as antibiotics and toxic analogues, involve similar principles to those concerning metals. Potentially, models for selection of resistance to any substance can be derived using this approach. | 1995 | 7766205 |
| 9310 | 6 | 0.9999 | Bacterial resistance to antibiotics. Effective antibacterial drugs have been available for nearly 50 years. After the introduction of each new such drug, whether chemically synthesized or a naturally occurring antibiotic, bacterial resistance to it has emerged. The genetic mechanisms by which bacteria have acquired resistance were quite unexpected; a new evolutionary pathways has been revealed. Although some antibiotic resistance has resulted from mutational changes in structural proteins--targets for the drugs' action--most has resulted from the acquisition of new, ready-made genes from an external source--that is, from another bacterium. Vectors of the resistance genes are plasmids--heritable DNA molecules that are transmissible between bacterial cells. Plasmids without antibiotic-resistance genes are common in all kinds of bacteria. Resistance plasmids have resulted from the insertion of new DNA sequences into previously existing plasmids. Thus, the spread of antibiotic resistance is at three levels: bacteria between people or animals; plasmids between bacteria; and transposable genes between plasmids. | 1984 | 6319093 |
| 3837 | 7 | 0.9999 | Evolutionary Paths That Expand Plasmid Host-Range: Implications for Spread of Antibiotic Resistance. The World Health Organization has declared the emergence of antibiotic resistance to be a global threat to human health. Broad-host-range plasmids have a key role in causing this health crisis because they transfer multiple resistance genes to a wide range of bacteria. To limit the spread of antibiotic resistance, we need to gain insight into the mechanisms by which the host range of plasmids evolves. Although initially unstable plasmids have been shown to improve their persistence through evolution of the plasmid, the host, or both, the means by which this occurs are poorly understood. Here, we sought to identify the underlying genetic basis of expanded plasmid host-range and increased persistence of an antibiotic resistance plasmid using a combined experimental-modeling approach that included whole-genome resequencing, molecular genetics and a plasmid population dynamics model. In nine of the ten previously evolved clones, changes in host and plasmid each slightly improved plasmid persistence, but their combination resulted in a much larger improvement, which indicated positive epistasis. The only genetic change in the plasmid was the acquisition of a transposable element from a plasmid native to the Pseudomonas host used in these studies. The analysis of genetic deletions showed that the critical genes on this transposon encode a putative toxin-antitoxin (TA) and a cointegrate resolution system. As evolved plasmids were able to persist longer in multiple naïve hosts, acquisition of this transposon also expanded the plasmid's host range, which has important implications for the spread of antibiotic resistance. | 2016 | 26668183 |
| 9435 | 8 | 0.9999 | Why are bacteria refractory to antimicrobials? The incidence of antibiotic resistance in pathogenic bacteria is rising. Antibiotic resistance can be achieved via three distinct routes: inactivation of the drug, modification of the target of action, and reduction in the concentration of drug that reaches the target. It has long been recognized that specific antibiotic resistance mechanisms can be acquired through mutation of the bacterial genome or by gaining additional genes through horizontal gene transfer. Recent attention has also brought to light the importance of different physiological states for the survival of bacteria in the presence of antibiotics. It is now apparent that bacteria have complex, intrinsic resistance mechanisms that are often not detected in the standard antibiotic sensitivity tests performed in clinical laboratories. The development of resistance in bacteria found in surface-associated aggregates or biofilms, owing to these intrinsic mechanisms, is paramount. | 2002 | 12354553 |
| 3827 | 9 | 0.9999 | The fitness cost of horizontally transferred and mutational antimicrobial resistance in Escherichia coli. Antimicrobial resistance (AMR) in bacteria implies a tradeoff between the benefit of resistance under antimicrobial selection pressure and the incurred fitness cost in the absence of antimicrobials. The fitness cost of a resistance determinant is expected to depend on its genetic support, such as a chromosomal mutation or a plasmid acquisition, and on its impact on cell metabolism, such as an alteration in an essential metabolic pathway or the production of a new enzyme. To provide a global picture of the factors that influence AMR fitness cost, we conducted a systematic review and meta-analysis focused on a single species, Escherichia coli. By combining results from 46 high-quality studies in a multilevel meta-analysis framework, we find that the fitness cost of AMR is smaller when provided by horizontally transferable genes such as those encoding beta-lactamases, compared to mutations in core genes such as those involved in fluoroquinolone and rifampicin resistance. We observe that the accumulation of acquired AMR genes imposes a much smaller burden on the host cell than the accumulation of AMR mutations, and we provide quantitative estimates of the additional cost of a new gene or mutation. These findings highlight that gene acquisition is more efficient than the accumulation of mutations to evolve multidrug resistance, which can contribute to the observed dominance of horizontally transferred genes in the current AMR epidemic. | 2023 | 37455716 |
| 9436 | 10 | 0.9999 | Phenotypic Resistance to Antibiotics. The development of antibiotic resistance is usually associated with genetic changes, either to the acquisition of resistance genes, or to mutations in elements relevant for the activity of the antibiotic. However, in some situations resistance can be achieved without any genetic alteration; this is called phenotypic resistance. Non-inherited resistance is associated to specific processes such as growth in biofilms, a stationary growth phase or persistence. These situations might occur during infection but they are not usually considered in classical susceptibility tests at the clinical microbiology laboratories. Recent work has also shown that the susceptibility to antibiotics is highly dependent on the bacterial metabolism and that global metabolic regulators can modulate this phenotype. This modulation includes situations in which bacteria can be more resistant or more susceptible to antibiotics. Understanding these processes will thus help in establishing novel therapeutic approaches based on the actual susceptibility shown by bacteria during infection, which might differ from that determined in the laboratory. In this review, we discuss different examples of phenotypic resistance and the mechanisms that regulate the crosstalk between bacterial metabolism and the susceptibility to antibiotics. Finally, information on strategies currently under development for diminishing the phenotypic resistance to antibiotics of bacterial pathogens is presented. | 2013 | 27029301 |
| 9697 | 11 | 0.9998 | Origins and evolution of antibiotic resistance. The massive prescription of antibiotics and their non-regulated and extensive usage has resulted in the development of extensive antibiotic resistance in microorganisms; this has been of great clinical significance. Antibiotic resistance occurs not only by mutation of microbial genes which code for antibiotic uptake into cells or the binding sites for antibiotics, but mostly by the acquisition of heterologous resistance genes from external sources. The physical characteristics of the microbial community play a major role in gene exchange, but antimicrobial agents provide the selective pressure for the development of resistance and promote the transfer of resistance genes among bacteria. The control of antibiotic usage is essential to prevent the development of resistance to new antibiotics. | 1996 | 9019139 |
| 9420 | 12 | 0.9998 | The intrinsic resistance of bacteria. Antibiotic resistance is often considered to be a trait acquired by previously susceptible bacteria, on the basis of which can be attributed to the horizontal acquisition of new genes or the occurrence of spontaneous mutation. In addition to acquired resistance, bacteria have a trait of intrinsic resistance to different classes of antibiotics. An intrinsic resistance gene is involved in intrinsic resistance, and its presence in bacterial strains is independent of previous antibiotic exposure and is not caused by horizontal gene transfer. Recently, interest in intrinsic resistance genes has increased, because these gene products not only may provide attractive therapeutic targets for development of novel drugs that rejuvenate the activity of existing antibiotics, and but also might predict future emergence of resistant pathogens if they become mobilized. In the present review, we summarize the conventional examples of intrinsic resistance, including the impermeability of cellular envelopes, the activity of multidrug efflux pumps or lack of drug targets. We also demonstrate that transferases and enzymes involved in basic bacterial metabolic processes confer intrinsic resistance in Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. We present as well information on the cryptic intrinsic resistance genes that do not confer resistance to their native hosts but are capable of conferring resistance when their expression levels are increased and the activation of the cryptic genes. Finally, we discuss that intrinsic genes could be the origin of acquired resistance, especially in the genus Acinetobacter. | 2016 | 27806928 |
| 6335 | 13 | 0.9998 | Gene Amplification Uncovers Large Previously Unrecognized Cryptic Antibiotic Resistance Potential in E. coli. The activation of unrecognized antibiotic resistance genes in the bacterial cell can give rise to antibiotic resistance without the need for major mutations or horizontal gene transfer. We hypothesize that bacteria harbor an extensive array of diverse cryptic genes that can be activated in response to antibiotics via adaptive resistance. To test this hypothesis, we developed a plasmid assay to randomly manipulate gene copy numbers in Escherichia coli cells and identify genes that conferred resistance when amplified. We then tested for cryptic resistance to 18 antibiotics and identified genes conferring resistance. E. coli could become resistant to 50% of the antibiotics tested, including chloramphenicol, d-cycloserine, polymyxin B, and 6 beta-lactam antibiotics, following this manipulation. Known antibiotic resistance genes comprised 13% of the total identified genes, where 87% were unclassified (cryptic) antibiotic resistance genes. These unclassified genes encoded cell membrane proteins, stress response/DNA repair proteins, transporters, and miscellaneous or hypothetical proteins. Stress response/DNA repair genes have a broad antibiotic resistance potential, as this gene class, in aggregate, conferred cryptic resistance to nearly all resistance-positive antibiotics. We found that antibiotics that are hydrophilic, those that are amphipathic, and those that inhibit the cytoplasmic membrane or cell wall biosynthesis were more likely to induce cryptic resistance in E. coli. This study reveals a diversity of cryptic genes that confer an antibiotic resistance phenotype when present in high copy number. Thus, our assay can identify potential novel resistance genes while also describing which antibiotics are prone to induce cryptic antibiotic resistance in E. coli. IMPORTANCE Predicting where new antibiotic resistance genes will rise is a challenge and is especially important when new antibiotics are developed. Adaptive resistance allows sensitive bacterial cells to become transiently resistant to antibiotics. This provides an opportune time for cells to develop more efficient resistance mechanisms, such as tolerance and permanent resistance to higher antibiotic concentrations. The biochemical diversity harbored within bacterial genomes may lead to the presence of genes that could confer resistance when timely activated. Therefore, it is crucial to understand adaptive resistance to identify potential resistance genes and prolong antibiotics. Here, we investigate cryptic resistance, an adaptive resistance mechanism, and identify unknown (cryptic) antibiotic resistance genes that confer resistance when amplified in a laboratory strain of E. coli. We also pinpoint antibiotic characteristics that are likely to induce cryptic resistance. This study may help detect novel antibiotic resistance genes and provide the foundation to help develop more effective antibiotics. | 2021 | 34756069 |
| 9614 | 14 | 0.9998 | Antibiotic-Independent Adaptive Effects of Antibiotic Resistance Mutations. Antibiotic usage selects for the accumulation and spread of antibiotic-resistant bacteria. However, resistance can also accumulate in the absence of antibiotic exposure. Antibiotics are often designed to target widely distributed regulatory housekeeping genes. The targeting of such genes enables these antibiotics to be useful against a wider variety of pathogens. This review highlights work suggesting that regulatory housekeeping genes of the type targeted by many antibiotics function as hubs of adaptation to conditions unrelated to antibiotic exposure. As a result of this, some mutations to the regulatory housekeeping gene targets of antibiotics confer both antibiotic resistance and an adaptive effect unrelated to antibiotic exposure. Such antibiotic-independent adaptive effects of resistance mutations may substantially affect the dynamics of antibiotic resistance accumulation and spread. | 2017 | 28629950 |
| 9312 | 15 | 0.9998 | Why There Are No Essential Genes on Plasmids. Mobile genetic elements such as plasmids are important for the evolution of prokaryotes. It has been suggested that there are differences between functions coded for by mobile genes and those in the "core" genome and that these differences can be seen between plasmids and chromosomes. In particular, it has been suggested that essential genes, such as those involved in the formation of structural proteins or in basic metabolic functions, are rarely located on plasmids. We model competition between genotypically varying bacteria within a single population to investigate whether selection favors a chromosomal location for essential genes. We find that in general, chromosomal locations for essential genes are indeed favored. This is because the inheritance of chromosomes is more stable than that for plasmids. We define the "degradation" rate as the rate at which chance genetic processes, for example, mutation, deletion, or translocation, render essential genes nonfunctioning. The only way in which plasmids can be a location for functioning essential genes is if chromosomal genes degrade faster than plasmid genes. If the two degradation rates are equal, or if plasmid genes degrade faster than chromosomal genes, functioning essential genes will be found only on chromosomes. | 2015 | 25540453 |
| 9311 | 16 | 0.9998 | Various plasmid strategies limit the effect of bacterial restriction-modification systems against conjugation. In bacteria, genes conferring antibiotic resistance are mostly carried on conjugative plasmids, mobile genetic elements that spread horizontally between bacterial hosts. Bacteria carry defence systems that defend them against genetic parasites, but how effective these are against plasmid conjugation is poorly understood. Here, we study to what extent restriction-modification (RM) systems-by far the most prevalent bacterial defence systems-act as a barrier against plasmids. Using 10 different RM systems and 13 natural plasmids conferring antibiotic resistance in Escherichia coli, we uncovered variation in defence efficiency ranging from none to 105-fold protection. Further analysis revealed genetic features of plasmids that explain the observed variation in defence levels. First, the number of RM recognition sites present on the plasmids generally correlates with defence levels, with higher numbers of sites being associated with stronger defence. Second, some plasmids encode methylases that protect against restriction activity. Finally, we show that a high number of plasmids in our collection encode anti-restriction genes that provide protection against several types of RM systems. Overall, our results show that it is common for plasmids to encode anti-RM strategies, and that, as a consequence, RM systems form only a weak barrier for plasmid transfer by conjugation. | 2024 | 39413206 |
| 4262 | 17 | 0.9998 | Fitness cost of antibiotic susceptibility during bacterial infection. Advances in high-throughput DNA sequencing allow for a comprehensive analysis of bacterial genes that contribute to virulence in a specific infectious setting. Such information can yield new insights that affect decisions on how to best manage major public health issues such as the threat posed by increasing antimicrobial drug resistance. Much of the focus has been on the consequences of the selective advantage conferred on drug-resistant strains during antibiotic therapy. It is thought that the genetic and phenotypic changes that confer resistance also result in concomitant reductions in in vivo fitness, virulence, and transmission. However, experimental validation of this accepted paradigm is modest. Using a saturated transposon library of Pseudomonas aeruginosa, we identified genes across many functional categories and operons that contributed to maximal in vivo fitness during lung infections in animal models. Genes that bestowed both intrinsic and acquired antibiotic resistance provided a positive in vivo fitness advantage to P. aeruginosa during infection. We confirmed these findings in the pathogenic bacteria Acinetobacter baumannii and Vibrio cholerae using murine and rabbit infection models, respectively. Our results show that efforts to confront the worldwide increase in antibiotic resistance might be exacerbated by fitness advantages that enhance virulence in drug-resistant microbes. | 2015 | 26203082 |
| 8923 | 18 | 0.9998 | The Genome-Wide Interaction Network of Nutrient Stress Genes in Escherichia coli. Conventional efforts to describe essential genes in bacteria have typically emphasized nutrient-rich growth conditions. Of note, however, are the set of genes that become essential when bacteria are grown under nutrient stress. For example, more than 100 genes become indispensable when the model bacterium Escherichia coli is grown on nutrient-limited media, and many of these nutrient stress genes have also been shown to be important for the growth of various bacterial pathogens in vivo To better understand the genetic network that underpins nutrient stress in E. coli, we performed a genome-scale cross of strains harboring deletions in some 82 nutrient stress genes with the entire E. coli gene deletion collection (Keio) to create 315,400 double deletion mutants. An analysis of the growth of the resulting strains on rich microbiological media revealed an average of 23 synthetic sick or lethal genetic interactions for each nutrient stress gene, suggesting that the network defining nutrient stress is surprisingly complex. A vast majority of these interactions involved genes of unknown function or genes of unrelated pathways. The most profound synthetic lethal interactions were between nutrient acquisition and biosynthesis. Further, the interaction map reveals remarkable metabolic robustness in E. coli through pathway redundancies. In all, the genetic interaction network provides a powerful tool to mine and identify missing links in nutrient synthesis and to further characterize genes of unknown function in E. coli Moreover, understanding of bacterial growth under nutrient stress could aid in the development of novel antibiotic discovery platforms. IMPORTANCE: With the rise of antibiotic drug resistance, there is an urgent need for new antibacterial drugs. Here, we studied a group of genes that are essential for the growth of Escherichia coli under nutrient limitation, culture conditions that arguably better represent nutrient availability during an infection than rich microbiological media. Indeed, many such nutrient stress genes are essential for infection in a variety of pathogens. Thus, the respective proteins represent a pool of potential new targets for antibacterial drugs that have been largely unexplored. We have created all possible double deletion mutants through a genetic cross of nutrient stress genes and the E. coli deletion collection. An analysis of the growth of the resulting clones on rich media revealed a robust, dense, and complex network for nutrient acquisition and biosynthesis. Importantly, our data reveal new genetic connections to guide innovative approaches for the development of new antibacterial compounds targeting bacteria under nutrient stress. | 2016 | 27879333 |
| 8920 | 19 | 0.9998 | A systems biology approach to drug targets in Pseudomonas aeruginosa biofilm. Antibiotic resistance is an increasing problem in the health care system and we are in a constant race with evolving bacteria. Biofilm-associated growth is thought to play a key role in bacterial adaptability and antibiotic resistance. We employed a systems biology approach to identify candidate drug targets for biofilm-associated bacteria by imitating specific microenvironments found in microbial communities associated with biofilm formation. A previously reconstructed metabolic model of Pseudomonas aeruginosa (PA) was used to study the effect of gene deletion on bacterial growth in planktonic and biofilm-like environmental conditions. A set of 26 genes essential in both conditions was identified. Moreover, these genes have no homology with any human gene. While none of these genes were essential in only one of the conditions, we found condition-dependent genes, which could be used to slow growth specifically in biofilm-associated PA. Furthermore, we performed a double gene deletion study and obtained 17 combinations consisting of 21 different genes, which were conditionally essential. While most of the difference in double essential gene sets could be explained by different medium composition found in biofilm-like and planktonic conditions, we observed a clear effect of changes in oxygen availability on the growth performance. Eight gene pairs were found to be synthetic lethal in oxygen-limited conditions. These gene sets may serve as novel metabolic drug targets to combat particularly biofilm-associated PA. Taken together, this study demonstrates that metabolic modeling of human pathogens can be used to identify oxygen-sensitive drug targets and thus, that this systems biology approach represents a powerful tool to identify novel candidate antibiotic targets. | 2012 | 22523548 |