# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 9436 | 0 | 1.0000 | 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 |
| 9435 | 1 | 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 |
| 9420 | 2 | 0.9999 | 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 |
| 9697 | 3 | 0.9999 | 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 |
| 9431 | 4 | 0.9999 | Biofilms and antimicrobial resistance. The pathogenesis of many orthopaedic infections is related to the presence of microorganisms in biofilms. I examine the emerging understanding of the mechanisms of biofilm-associated antimicrobial resistance. Biofilm-associated resistance to antimicrobial agents begins at the attachment phase and increases as the biofilm ages. A variety of reasons for the increased antimicrobial resistance of microorganisms in biofilms have been postulated and investigated. Although bacteria in biofilms are surrounded by an extracellular matrix that might physically restrict the diffusion of antimicrobial agents, this does not seem to be a predominant mechanism of biofilm-associated antimicrobial resistance. Nutrient and oxygen depletion within the biofilm cause some bacteria to enter a nongrowing (ie, stationary) state, in which they are less susceptible to growth-dependent antimicrobial killing. A subpopulation of bacteria might differentiate into a phenotypically resistant state. Finally, some organisms in biofilms have been shown to express biofilm-specific antimicrobial resistance genes that are not required for biofilm formation. Overall, the mechanism of biofilm-associated antimicrobial resistance seems to be multifactorial and may vary from organism to organism. Techniques that address biofilm susceptibility testing to antimicrobial agents may be necessary before antimicrobial regimens for orthopaedic prosthetic device-associated infections can be appropriately defined in research and clinical settings. Finally, a variety of approaches are being defined to overcome biofilm-associated antimicrobial resistance. | 2005 | 16056024 |
| 9421 | 5 | 0.9999 | The neglected intrinsic resistome of bacterial pathogens. Bacteria with intrinsic resistance to antibiotics are a worrisome health problem. It is widely believed that intrinsic antibiotic resistance of bacterial pathogens is mainly the consequence of cellular impermeability and activity of efflux pumps. However, the analysis of transposon-tagged Pseudomonas aeruginosa mutants presented in this article shows that this phenotype emerges from the action of numerous proteins from all functional categories. Mutations in some genes make P. aeruginosa more susceptible to antibiotics and thereby represent new targets. Mutations in other genes make P. aeruginosa more resistant and therefore define novel mechanisms for mutation-driven acquisition of antibiotic resistance, opening a new research field based in the prediction of resistance before it emerges in clinical environments. Antibiotics are not just weapons against bacterial competitors, but also natural signalling molecules. Our results demonstrate that antibiotic resistance genes are not merely protective shields and offer a more comprehensive view of the role of antibiotic resistance genes in the clinic and in nature. | 2008 | 18286176 |
| 4238 | 6 | 0.9999 | Biocide tolerance in bacteria. Biocides have been employed for centuries, so today a wide range of compounds showing different levels of antimicrobial activity have become available. At the present time, understanding the mechanisms of action of biocides has also become an important issue with the emergence of bacterial tolerance to biocides and the suggestion that biocide and antibiotic resistance in bacteria might be linked. While most of the mechanisms providing antibiotic resistance are agent specific, providing resistance to a single antimicrobial or class of antimicrobial, there are currently numerous examples of efflux systems that accommodate and, thus, provide tolerance to a broad range of structurally unrelated antimicrobials, both antibiotics and biocides. If biocide tolerance becomes increasingly common and it is linked to antibiotic resistance, not only resistant (even multi-resistant) bacteria could be passed along the food chain, but also there are resistance determinants that can spread and lead to the emergence of new resistant microorganisms, which can only be detected and monitored when the building blocks of resistance traits are understood on the molecular level. This review summarizes the main advances reached in understanding the mechanism of action of biocides, the mechanisms of bacterial resistance to both biocides and antibiotics, and the incidence of biocide tolerance in bacteria of concern to human health and the food industry. | 2013 | 23340387 |
| 9434 | 7 | 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 |
| 4262 | 8 | 0.9999 | 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 |
| 4264 | 9 | 0.9999 | Mutational Evolution of Pseudomonas aeruginosa Resistance to Ribosome-Targeting Antibiotics. The present work examines the evolutionary trajectories of replicate Pseudomonas aeruginosa cultures in presence of the ribosome-targeting antibiotics tobramycin and tigecycline. It is known that large number of mutations across different genes - and therefore a large number of potential pathways - may be involved in resistance to any single antibiotic. Thus, evolution toward resistance might, to a large degree, rely on stochasticity, which might preclude the use of predictive strategies for fighting antibiotic resistance. However, the present results show that P. aeruginosa populations evolving in parallel in the presence of antibiotics (either tobramycin or tigecycline) follow a set of trajectories that present common elements. In addition, the pattern of resistance mutations involved include common elements for these two ribosome-targeting antimicrobials. This indicates that mutational evolution toward resistance (and perhaps other properties) is to a certain degree deterministic and, consequently, predictable. These findings are of interest, not just for P. aeruginosa, but in understanding the general rules involved in the evolution of antibiotic resistance also. In addition, the results indicate that bacteria can evolve toward higher levels of resistance to antibiotics against which they are considered to be intrinsically resistant, as tigecycline in the case of P. aeruginosa and that this may confer cross-resistance to other antibiotics of therapeutic value. Our results are particularly relevant in the case of patients under empiric treatment with tigecycline, which frequently suffer P. aeruginosa superinfections. | 2018 | 30405685 |
| 9609 | 10 | 0.9999 | The classification of bacterial survival strategies in the presence of antimicrobials. The survival of bacteria under antibiotic therapy varies in nature and is based on the bacterial ability to employ a wide range of fundamentally different resistance mechanisms. This great diversity requires a disambiguation of the term 'resistance' and the development of a more precise classification of bacterial survival strategies during contact with antibiotics. The absence of a unified definition for the terms 'resistance', 'tolerance' and 'persistence' further aggravates the imperfections of the current classification system. This review suggests a number of original classification criteria that will take into account (1) the bacterial ability to replicate in the presence of antimicrobial agents, (2) existing evolutionary stability of a trait within a species, and (3) the presence or absence of specialized genes that determine the ability of a microorganism to decrease its own metabolism or switch it completely off. This review describes potential advantages of the suggested classification system, which include a better understanding of the relationship between bacterial survival in the presence of antibiotics and molecular mechanisms of cellular metabolism suppression, the opportunity to pinpoint targets to identify a true bacterial resistance profile. The true resistance profile in turn, could be used to develop effective diagnostic and antimicrobial therapy methods, while taking into consideration specific bacterial survival mechanisms. | 2021 | 33930413 |
| 4425 | 11 | 0.9999 | Multidrug resistance in bacteria. Large amounts of antibiotics used for human therapy, as well as for farm animals and even for fish in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. Multidrug resistance in bacteria may be generated by one of two mechanisms. First, these bacteria may accumulate multiple genes, each coding for resistance to a single drug, within a single cell. This accumulation occurs typically on resistance (R) plasmids. Second, multidrug resistance may also occur by the increased expression of genes that code for multidrug efflux pumps, extruding a wide range of drugs. This review discusses our current knowledge on the molecular mechanisms involved in both types of resistance. | 2009 | 19231985 |
| 4263 | 12 | 0.9999 | The emergence of antibiotic resistance by mutation. The emergence of mutations in nucleic acids is one of the major factors underlying evolution, providing the working material for natural selection. Most bacteria are haploid for the vast majority of their genes and, coupled with typically short generation times, this allows mutations to emerge and accumulate rapidly, and to effect significant phenotypic changes in what is perceived to be real-time. Not least among these phenotypic changes are those associated with antibiotic resistance. Mechanisms of horizontal gene spread among bacterial strains or species are often considered to be the main mediators of antibiotic resistance. However, mutational resistance has been invaluable in studies of bacterial genetics, and also has primary clinical importance in certain bacterial species, such as Mycobacterium tuberculosis and Helicobacter pylori, or when considering resistance to particular antibiotics, especially to synthetic agents such as fluoroquinolones and oxazolidinones. In addition, mutation is essential for the continued evolution of acquired resistance genes and has, e.g., given rise to over 100 variants of the TEM family of beta-lactamases. Hypermutator strains of bacteria, which have mutations in genes affecting DNA repair and replication fidelity, have elevated mutation rates. Mutational resistance emerges de novo more readily in these hypermutable strains, and they also provide a suitable host background for the evolution of acquired resistance genes in vitro. In the clinical setting, hypermutator strains of Pseudomonas aeruginosa have been isolated from the lungs of cystic fibrosis patients, but a more general role for hypermutators in the emergence of clinically relevant antibiotic resistance in a wider variety of bacterial pathogens has not yet been proven. | 2007 | 17184282 |
| 9683 | 13 | 0.9999 | Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world? Hosts and bacteria have coevolved over millions of years, during which pathogenic bacteria have modified their virulence mechanisms to adapt to host defense systems. Although the spread of pathogens has been hindered by the discovery and widespread use of antimicrobial agents, antimicrobial resistance has increased globally. The emergence of resistant bacteria has accelerated in recent years, mainly as a result of increased selective pressure. However, although antimicrobial resistance and bacterial virulence have developed on different timescales, they share some common characteristics. This review considers how bacterial virulence and fitness are affected by antibiotic resistance and also how the relationship between virulence and resistance is affected by different genetic mechanisms (e.g., coselection and compensatory mutations) and by the most prevalent global responses. The interplay between these factors and the associated biological costs depend on four main factors: the bacterial species involved, virulence and resistance mechanisms, the ecological niche, and the host. The development of new strategies involving new antimicrobials or nonantimicrobial compounds and of novel diagnostic methods that focus on high-risk clones and rapid tests to detect virulence markers may help to resolve the increasing problem of the association between virulence and resistance, which is becoming more beneficial for pathogenic bacteria. | 2013 | 23554414 |
| 4250 | 14 | 0.9999 | Intrinsic, adaptive and acquired antimicrobial resistance in Gram-negative bacteria. Gram-negative bacteria are responsible for a large proportion of antimicrobial-resistant infections in humans and animals. Among this class of bacteria are also some of the most successful environmental organisms. Part of this success is their adaptability to a variety of different niches, their intrinsic resistance to antimicrobial drugs and their ability to rapidly acquire resistance mechanisms. These mechanisms of resistance are not exclusive and the interplay of several mechanisms causes high levels of resistance. In this review, we explore the molecular mechanisms underlying resistance in Gram-negative organisms and how these different mechanisms enable them to survive many different stress conditions. | 2017 | 28258229 |
| 9288 | 15 | 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 |
| 9696 | 16 | 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 |
| 9492 | 17 | 0.9999 | The Search for 'Evolution-Proof' Antibiotics. The effectiveness of antibiotics has been widely compromised by the evolution of resistance among pathogenic bacteria. It would be restored by the development of antibiotics to which bacteria cannot evolve resistance. We first discuss two kinds of 'evolution-proof' antibiotic. The first comprises literally evolution-proof antibiotics to which bacteria cannot become resistant by mutation or horizontal gene transfer. The second category comprises agents to which resistance may arise, but so rarely that it does not become epidemic. The likelihood that resistance to a novel agent will spread is evaluated here by a simple model that includes biological and therapeutic parameters governing the evolution of resistance within hosts and the transmission of resistant strains between hosts. This model leads to the conclusion that epidemic spread is unlikely if the frequency of mutations that confer resistance falls below a defined minimum value, and it identifies potential targets for intervention to prevent the evolution of resistance. Whether or not evolution-proof antibiotics are ever found, searching for them is likely to improve the deployment of new and existing agents by advancing our understanding of how resistance evolves. | 2018 | 29191398 |
| 9614 | 18 | 0.9999 | 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 |
| 4241 | 19 | 0.9999 | Mechanisms of antimicrobial resistance and implications for epidemiology. The development of antibacterial agents has provided a means of treating bacterial diseases which were, previously, often fatal in both man and animal and thus represents one of the major advances of the 20th century. However, the efficacy of these agents is increasingly being compromised by the development of bacterial resistance to the drugs currently available for therapeutic use. Bacterial resistance can be combated in two ways. New drugs to which bacteria are susceptible can be developed and policies to contain the development and spread of resistance can be implemented. Both strategies require an understanding of the mechanisms of drug resistance, its epidemiology and the role of environmental factors in promoting resistance. Over the past thirty years our knowledge of bacterial resistance has increased dramatically mainly due to new technology that has become available. Bacteria are able to resist antibacterials by a variety of mechanisms: for example, altering the target to decrease susceptibility to the antibacterial, inactivating or destroying the drug, reducing drug transport into the cell or metabolic bypass. These drug resistance determinants are mediated via one of two distinct genetic mechanisms, a mutation in the bacterial chromosome or by a transmissible element; either a plasmid or a transposon. Significant differences exist between these two types of drug resistance as transmissible resistance, which is mainly plasmid-mediated, permits intraspecies and even interspecies transfer to occur. In contrast, chromosomal resistance can only be passed on to progeny. Transmissible antibacterial resistance is the major cause of concern as it can lead to the rapid spread of antibacterial resistance and has proven difficult, if not impossible, to eradicate. Furthermore, plasmids and transposons can code for multiple antibiotic resistance as well as virulence genes. Antibacterials for which transferable resistance has been identified include most commonly used antibacterials such as beta-lactams, aminoglycosides, macrolides, sulphonamides, tetracyclines, chloramphenicol and trimethoprim. One notable exception is the 4-quinolones for which plasmid-mediated resistance has yet to be identified. | 1993 | 8212509 |