# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 3829 | 0 | 1.0000 | Associations among Antibiotic and Phage Resistance Phenotypes in Natural and Clinical Escherichia coli Isolates. The spread of antibiotic resistance is driving interest in new approaches to control bacterial pathogens. This includes applying multiple antibiotics strategically, using bacteriophages against antibiotic-resistant bacteria, and combining both types of antibacterial agents. All these approaches rely on or are impacted by associations among resistance phenotypes (where bacteria resistant to one antibacterial agent are also relatively susceptible or resistant to others). Experiments with laboratory strains have shown strong associations between some resistance phenotypes, but we lack a quantitative understanding of associations among antibiotic and phage resistance phenotypes in natural and clinical populations. To address this, we measured resistance to various antibiotics and bacteriophages for 94 natural and clinical Escherichia coli isolates. We found several positive associations between resistance phenotypes across isolates. Associations were on average stronger for antibacterial agents of the same type (antibiotic-antibiotic or phage-phage) than different types (antibiotic-phage). Plasmid profiles and genetic knockouts suggested that such associations can result from both colocalization of resistance genes and pleiotropic effects of individual resistance mechanisms, including one case of antibiotic-phage cross-resistance. Antibiotic resistance was predicted by core genome phylogeny and plasmid profile, but phage resistance was predicted only by core genome phylogeny. Finally, we used observed associations to predict genes involved in a previously uncharacterized phage resistance mechanism, which we verified using experimental evolution. Our data suggest that susceptibility to phages and antibiotics are evolving largely independently, and unlike in experiments with lab strains, negative associations between antibiotic resistance phenotypes in nature are rare. This is relevant for treatment scenarios where bacteria encounter multiple antibacterial agents.IMPORTANCE Rising antibiotic resistance is making it harder to treat bacterial infections. Whether resistance to a given antibiotic spreads or declines is influenced by whether it is associated with altered susceptibility to other antibiotics or other stressors that bacteria encounter in nature, such as bacteriophages (viruses that infect bacteria). We used natural and clinical isolates of Escherichia coli, an abundant species and key pathogen, to characterize associations among resistance phenotypes to various antibiotics and bacteriophages. We found associations between some resistance phenotypes, and in contrast to past work with laboratory strains, they were exclusively positive. Analysis of bacterial genome sequences and horizontally transferred genetic elements (plasmids) helped to explain this, as well as our finding that there was no overall association between antibiotic resistance and bacteriophage resistance profiles across isolates. This improves our understanding of resistance evolution in nature, potentially informing new rational therapies that combine different antibacterials, including bacteriophages. | 2017 | 29089428 |
| 3830 | 1 | 0.9999 | Resistance Gene Carriage Predicts Growth of Natural and Clinical Escherichia coli Isolates in the Absence of Antibiotics. Bacterial pathogens that carry antibiotic resistance alleles sometimes pay a cost in the form of impaired growth in antibiotic-free conditions. This cost of resistance is expected to be a key parameter for understanding how resistance spreads and persists in pathogen populations. Analysis of individual resistance alleles from laboratory evolution and natural isolates has shown they are typically costly, but these costs are highly variable and influenced by genetic variation at other loci. It therefore remains unclear how strongly resistance is linked to impaired antibiotic-free growth in bacteria from natural and clinical scenarios, where resistance alleles are likely to coincide with other types of genetic variation. To investigate this, we measured the growth of 92 natural and clinical Escherichia coli isolates across three antibiotic-free environments. We then tested whether variation of antibiotic-free growth among isolates was predicted by their resistance to 10 antibiotics, while accounting for the phylogenetic structure of the data. We found that isolates with similar resistance profiles had similar antibiotic-free growth profiles, but it was not simply that higher average resistance was associated with impaired growth. Next, we used whole-genome sequences to identify antibiotic resistance genes and found that isolates carrying a greater number of resistance gene types grew relatively poorly in antibiotic-free conditions, even when the resistance genes they carried were different. This suggests that the resistance of bacterial pathogens is linked to growth costs in nature, but it is the total genetic burden and multivariate resistance phenotype that predict these costs, rather than individual alleles or mean resistance across antibiotics.IMPORTANCE Managing the spread of antibiotic resistance in bacterial pathogens is a major challenge for global public health. Central to this challenge is understanding whether resistance is linked to impaired bacterial growth in the absence of antibiotics, because this determines whether resistance declines when bacteria are no longer exposed to antibiotics. We studied 92 isolates of the key bacterial pathogen Escherichia coli; these isolates varied in both their antibiotic resistance genes and other parts of the genome. Taking this approach, rather than focusing on individual genetic changes associated with resistance as in much previous work, revealed that growth without antibiotics was linked to the number of specialized resistance genes carried and the combination of antibiotics to which isolates were resistant but was not linked to average antibiotic resistance. This approach provides new insights into the genetic factors driving the long-term persistence of antibiotic-resistant bacteria, which is important for future efforts to predict and manage resistance. | 2019 | 30530714 |
| 3832 | 2 | 0.9999 | A population genomics approach to exploiting the accessory 'resistome' of Escherichia coli. The emergence of antibiotic resistance is a defining challenge, and Escherichia coli is recognized as one of the leading species resistant to the antimicrobials used in human or veterinary medicine. Here, we analyse the distribution of 2172 antimicrobial-resistance (AMR) genes in 4022 E. coli to provide a population-level view of resistance in this species. By separating the resistance determinants into 'core' (those found in all strains) and 'accessory' (those variably present) determinants, we have found that, surprisingly, almost half of all E. coli do not encode any accessory resistance determinants. However, those strains that do encode accessory resistance are significantly more likely to be resistant to multiple antibiotic classes than would be expected by chance. Furthermore, by studying the available date of isolation for the E. coli genomes, we have visualized an expanding, highly interconnected network that describes how resistances to antimicrobials have co-associated within genomes over time. These data can be exploited to reveal antimicrobial combinations that are less likely to be found together, and so if used in combination may present an increased chance of suppressing the growth of bacteria and reduce the rate at which resistance factors are spread. Our study provides a complex picture of AMR in the E. coli population. Although the incidence of resistance to all studied antibiotic classes has increased dramatically over time, there exist combinations of antibiotics that could, in theory, attack the entirety of E. coli, effectively removing the possibility that discrete AMR genes will increase in frequency in the population. | 2017 | 28785420 |
| 4340 | 3 | 0.9999 | Predicting antimicrobial susceptibility from the bacterial genome: A new paradigm for one health resistance monitoring. The laboratory identification of antibacterial resistance is a cornerstone of infectious disease medicine. In vitro antimicrobial susceptibility testing has long been based on the growth response of organisms in pure culture to a defined concentration of antimicrobial agents. By comparing individual isolates to wild-type susceptibility patterns, strains with acquired resistance can be identified. Acquired resistance can also be detected genetically. After many decades of research, the inventory of genes underlying antimicrobial resistance is well known for several pathogenic genera including zoonotic enteric organisms such as Salmonella and Campylobacter and continues to grow substantially for others. With the decline in costs for large scale DNA sequencing, it is now practicable to characterize bacteria using whole genome sequencing, including the carriage of resistance genes in individual microorganisms and those present in complex biological samples. With genomics, we can generate comprehensive, detailed information on the bacterium, the mechanisms of antibiotic resistance, clues to its source, and the nature of mobile DNA elements by which resistance spreads. These developments point to a new paradigm for antimicrobial resistance detection and tracking for both clinical and public health purposes. | 2021 | 33010049 |
| 4050 | 4 | 0.9999 | Are Virulence and Antibiotic Resistance Genes Linked? A Comprehensive Analysis of Bacterial Chromosomes and Plasmids. Although pathogenic bacteria are the targets of antibiotics, these drugs also affect hundreds of commensal or mutualistic species. Moreover, the use of antibiotics is not only restricted to the treatment of infections but is also largely applied in agriculture and in prophylaxis. During this work, we tested the hypothesis that there is a correlation between the number and the genomic location of antibiotic resistance (AR) genes and virulence factor (VF) genes. We performed a comprehensive study of 16,632 reference bacterial genomes in which we identified and counted all orthologues of AR and VF genes in each of the locations: chromosomes, plasmids, or in both locations of the same genome. We found that, on a global scale, no correlation emerges. However, some categories of AR and VF genes co-occur preferentially, and in the mobilome, which supports the hypothesis that some bacterial pathogens are under selective pressure to be resistant to specific antibiotics, a fact that can jeopardize antimicrobial therapy for some human-threatening diseases. | 2022 | 35740113 |
| 9922 | 5 | 0.9999 | De novo acquisition of antibiotic resistance in six species of bacteria. Bacteria can become resistant to antibiotics in two ways: by acquiring resistance genes through horizontal gene transfer and by de novo development of resistance upon exposure to non-lethal concentrations. The importance of the second process, de novo build-up, has not been investigated systematically over a range of species and may be underestimated as a result. To investigate the DNA mutation patterns accompanying the de novo antibiotic resistance acquisition process, six bacterial species encountered in the food chain were exposed to step-wise increasing sublethal concentrations of six antibiotics to develop high levels of resistance. Phenotypic and mutational landscapes were constructed based on whole-genome sequencing at two time points of the evolutionary trajectory. In this study, we found that (1) all of the six strains can develop high levels of resistance against most antibiotics; (2) increased resistance is accompanied by different mutations for each bacterium-antibiotic combination; (3) the number of mutations varies widely, with Y. enterocolitica having by far the most; (4) in the case of fluoroquinolone resistance, a mutational pattern of gyrA combined with parC is conserved in five of six species; and (5) mutations in genes coding for efflux pumps are widely encountered in gram-negative species. The overall conclusion is that very similar phenotypic outcomes are instigated by very different genetic changes. The outcome of this study may assist policymakers when formulating practical strategies to prevent development of antimicrobial resistance in human and veterinary health care.IMPORTANCEMost studies on de novo development of antimicrobial resistance have been performed on Escherichia coli. To examine whether the conclusions of this research can be applied to more bacterial species, six species of veterinary importance were made resistant to six antibiotics, each of a different class. The rapid build-up of resistance observed in all six species upon exposure to non-lethal concentrations of antimicrobials indicates a similar ability to adjust to the presence of antibiotics. The large differences in the number of DNA mutations accompanying de novo resistance suggest that the mechanisms and pathways involved may differ. Hence, very similar phenotypes can be the result of various genotypes. The implications of the outcome are to be considered by policymakers in the area of veterinary and human healthcare. | 2025 | 39907470 |
| 3831 | 6 | 0.9999 | The distribution of fitness effects of plasmid pOXA-48 in clinical enterobacteria. Antimicrobial resistance (AMR) in bacteria is a major public health problem. The main route for AMR acquisition in clinically important bacteria is the horizontal transfer of plasmids carrying resistance genes. AMR plasmids allow bacteria to survive antibiotics, but they also entail physiological alterations in the host cell. Multiple studies over the last few years have indicated that these alterations can translate into a fitness cost when antibiotics are absent. However, due to technical limitations, most of these studies are based on analysing new associations between plasmids and bacteria generated in vitro, and we know very little about the effects of plasmids in their native bacterial hosts. In this study, we used a CRISPR-Cas9-tool to selectively cure plasmids from clinical enterobacteria to overcome this limitation. Using this approach, we were able to study the fitness effects of the carbapenem resistance plasmid pOXA-48 in 35 pOXA-48-carrying isolates recovered from hospitalized patients. Our results revealed that pOXA-48 produces variable effects across the collection of wild-type enterobacterial strains naturally carrying the plasmid, ranging from fitness costs to fitness benefits. Importantly, the plasmid was only associated with a significant fitness reduction in four out of 35 clones, and produced no significant changes in fitness in the great majority of isolates. Our results suggest that plasmids produce neutral fitness effects in most native bacterial hosts, helping to explain the great prevalence of plasmids in natural microbial communities. | 2023 | 37505800 |
| 9920 | 7 | 0.9999 | Designing antibiotic cycling strategies by determining and understanding local adaptive landscapes. The evolution of antibiotic resistance among bacteria threatens our continued ability to treat infectious diseases. The need for sustainable strategies to cure bacterial infections has never been greater. So far, all attempts to restore susceptibility after resistance has arisen have been unsuccessful, including restrictions on prescribing [1] and antibiotic cycling [2], [3]. Part of the problem may be that those efforts have implemented different classes of unrelated antibiotics, and relied on removal of resistance by random loss of resistance genes from bacterial populations (drift). Here, we show that alternating structurally similar antibiotics can restore susceptibility to antibiotics after resistance has evolved. We found that the resistance phenotypes conferred by variant alleles of the resistance gene encoding the TEM β-lactamase (bla(TEM)) varied greatly among 15 different β-lactam antibiotics. We captured those differences by characterizing complete adaptive landscapes for the resistance alleles bla(TEM-50) and bla(TEM-85), each of which differs from its ancestor bla(TEM-1) by four mutations. We identified pathways through those landscapes where selection for increased resistance moved in a repeating cycle among a limited set of alleles as antibiotics were alternated. Our results showed that susceptibility to antibiotics can be sustainably renewed by cycling structurally similar antibiotics. We anticipate that these results may provide a conceptual framework for managing antibiotic resistance. This approach may also guide sustainable cycling of the drugs used to treat malaria and HIV. | 2013 | 23418506 |
| 4180 | 8 | 0.9999 | Toward integrative genomics study of genetic resistance to Salmonella and Campylobacter intestinal colonization in fowl. Salmonella enterica serotypes Enteritidis and Typhimurium and Campylobacter jejuni are responsible for most cases of food poisoning in Europe. These bacteria do not cause severe disease symptoms in chicken, but they are easily propagated by symptomless chicken carriers which cannot be easily isolated. This animal tolerance is detrimental to food safety. In this particular case, increasing animal's resistance is not sufficient, since some animals considered as resistant are able to carry bacteria during several weeks without displaying disease symptoms. We review studies aimed at evaluating the resistance of chicken to Salmonella and Campylobacter intestinal colonization, either a few days or several weeks after infection. While studies of the genetic control of Campylobacter colonization are only beginning, mostly due to technical difficulties in infection protocols, genetic studies of Salmonella colonization have been conducted for now more than 20 years. They have initially reported an estimation of the genetic parameters associated with resistance to Salmonella colonization and are now aimed at identifying the genomic regions controlling variation of this trait in experimental lines and commercial populations. With the advent of high-throughput genomics, we are closer than ever to identify the true genes controlling resistance to Enterobacteria colonization in chicken. The comparison of genes involved in early resistance to intestinal colonization with genes controlling resistance to bacteria persistence several weeks after infection (i.e., carrier-state) should soon highlight the differences between the molecular mechanisms underlying those two distinct phenotypes. It will also be highly interesting to compare the genes or genomic regions controlling Campylobacter and Salmonella, in order to evaluate the feasibility of a selection conducted on both bacteria simultaneously. | 2012 | 23412643 |
| 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 |
| 3828 | 10 | 0.9999 | Interaction with a phage gene underlie costs of a β-lactamase. The fitness cost of an antibiotic resistance gene (ARG) can differ across host strains, creating refuges that allow the maintenance of an ARG in the absence of direct selection for its resistance phenotype. Despite the importance of such ARG-host interactions for predicting ARG dynamics, the basis of ARG fitness costs and their variability between hosts are not well understood. We determined the genetic basis of a host-dependent cost of a β-lactamase, bla(TEM-116*), that conferred a significant cost in one Escherichia coli strain but was close to neutral in 11 other Escherichia spp. strains. Selection of a bla(TEM-116*)-encoding plasmid in the strain in which it initially had a high cost resulted in rapid and parallel compensation for that cost through mutations in a P1-like phage gene, relA(P1). When the wild-type relA(P1) gene was added to a strain in which it was not present and in which bla(TEM-116*) was neutral, it caused the ARG to become costly. Thus, relA(P1) is both necessary and sufficient to explain bla(TEM-116*) costs in at least some host backgrounds. To our knowledge, these findings represent the first demonstrated case of the cost of an ARG being influenced by a genetic interaction with a phage gene. The interaction between a phage gene and a plasmid-borne ARG highlights the complexity of selective forces determining the maintenance and spread of ARGs and, by extension, encoding phage and plasmids in natural bacterial communities.IMPORTANCEAntibiotic resistance genes (ARGs) play a major role in the increasing problem of antibiotic resistance in clinically relevant bacteria. Selection of these genes occurs in the presence of antibiotics, but their eventual success also depends on the sometimes substantial costs they impose on host bacteria in antibiotic-free environments. We evolved an ARG that confers resistance to penicillin-type antibiotics in one host in which it did confer a cost and in one host in which it did not. We found that costs were rapidly and consistently reduced through parallel genetic changes in a gene encoded by a phage that was infecting the costly host. The unmutated version of this gene was sufficient to cause the ARG to confer a cost in a host in which it was originally neutral, demonstrating an antagonism between the two genetic elements and underlining the range and complexity of pressures determining ARG dynamics in natural populations. | 2024 | 38194254 |
| 9662 | 11 | 0.9999 | Species-Scale Genomic Analysis of Staphylococcus aureus Genes Influencing Phage Host Range and Their Relationships to Virulence and Antibiotic Resistance Genes. Phage therapy has been proposed as a possible alternative treatment for infections caused by the ubiquitous bacterial pathogen Staphylococcus aureus. However, successful therapy requires understanding the genetic basis of host range-the subset of strains in a species that could be killed by a particular phage. We searched diverse sets of S. aureus public genome sequences against a database of genes suggested from prior studies to influence host range to look for patterns of variation across the species. We found that genes encoding biosynthesis of molecules that were targets of S. aureus phage adsorption to the outer surface of the cell were the most conserved in the pangenome. Putative phage resistance genes that were core components of the pangenome genes had similar nucleotide diversity, ratio of nonsynonymous to synonymous substitutions, and functionality (measured by delta-bitscore) to other core genes. However, phage resistance genes that were not part of the core genome were significantly less consistent with the core genome phylogeny than all noncore genes in this set, suggesting more frequent movement between strains by horizontal gene transfer. Only superinfection immunity genes encoded by temperate phages inserted in the genome correlated with experimentally determined temperate phage resistance. Taken together, these results suggested that, while phage adsorption genes are heavily conserved in the S. aureus species, HGT may play a significant role in strain-specific evolution of host range patterns. IMPORTANCE Staphylococcus aureus is a widespread, hospital- and community-acquired pathogen that is commonly antibiotic resistant. It causes diverse diseases affecting both the skin and internal organs. Its ubiquity, antibiotic resistance, and disease burden make new therapies urgent, such as phage therapy, in which viruses specific to infecting bacteria clear infection. S. aureus phage host range not only determines whether phage therapy will be successful by killing bacteria but also horizontal gene transfer through transduction of host genetic material by phages. In this work, we comprehensively reviewed existing literature to build a list of S. aureus phage resistance genes and searched our database of almost 43,000 S. aureus genomes for these genes to understand their patterns of evolution, finding that prophages' superinfection immunity correlates best with phage resistance and HGT. These findings improved our understanding of the relationship between known phage resistance genes and phage host range in the species. | 2022 | 35040700 |
| 4267 | 12 | 0.9999 | Relationship between Virulence and Resistance among Gram-Negative Bacteria. Bacteria present in the human body are innocuous, providing beneficial functions, some of which are necessary for correct body function. However, other bacteria are able to colonize, invade, and cause damage to different tissues, and these are categorised as pathogens. These pathogenic bacteria possess several factors that enable them to be more virulent and cause infection. Bacteria have a great capacity to adapt to different niches and environmental conditions (presence of antibiotics, iron depletion, etc.). Antibiotic pressure has favoured the emergence and spread of antibiotic-resistant bacteria worldwide. Several studies have reported the presence of a relationship (both positive and negative, and both direct and indirect) between antimicrobial resistance and virulence among bacterial pathogens. This review studies the relationship among the most important Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) taking into account two points of view: (i) the effect the acquisition of resistance has on virulence, and (ii) co-selection of resistance and virulence. The relationship between resistance and virulence among bacteria depends on the bacterial species, the specific mechanisms of resistance and virulence, the ecological niche, and the host. | 2020 | 33092201 |
| 4266 | 13 | 0.9999 | Novel Bacteriophages Capable of Disrupting Biofilms From Clinical Strains of Aeromonas hydrophila. The increase in global warming has favored growth of a range of opportunistic environmental bacteria and allowed some of these to become more pathogenic to humans. Aeromonas hydrophila is one such organism. Surviving in moist conditions in temperate climates, these bacteria have been associated with a range of diseases in humans, and in systemic infections can cause mortality in up to 46% of cases. Their capacity to form biofilms, carry antibiotic resistance mechanisms, and survive disinfection, has meant that they are not easily treated with traditional methods. Bacteriophage offer a possible alternative approach for controlling their growth. This study is the first to report the isolation and characterization of bacteriophages lytic against clinical strains of A. hydrophila which carry intrinsic antibiotic resistance genes. Functionally, these novel bacteriophages were shown to be capable of disrupting biofilms caused by clinical isolates of A. hydrophila. The potential exists for these to be tested in clinical and environmental settings. | 2020 | 32117183 |
| 3826 | 14 | 0.9999 | Co-resistance: an opportunity for the bacteria and resistance genes. Co-resistance involves transfer of several genes into the same bacteria and/or the acquisition of mutations in different genetic loci affecting different antimicrobials whereas pleiotropic resistance implies the same genetic event affecting several antimicrobials. There is an increasing prevalence of isolates with co-resistance which are over-represented within the so-called high-risk clones. Compensatory events avoid fitness cost of co-resistance, even in the absence of antimicrobials. Nevertheless, they might be selected by different antimicrobials and a single agent might select co-resistant isolates. This process, named as co-selection, is not avoided with cycling or mixing strategies of antimicrobial use. Co-resistance and co-selection processes increase the opportunity for persistence of the bacteria and resistance genes and should be considered when designing strategies for decreasing antimicrobial resistance. | 2011 | 21840259 |
| 4051 | 15 | 0.9999 | The human microbiome harbors a diverse reservoir of antibiotic resistance genes. The increasing levels of multi-drug resistance in human pathogenic bacteria are compromising our ability to treat infectious disease. Since antibiotic resistance determinants are readily exchanged between bacteria through lateral gene transfer, there is an increasing interest in investigating reservoirs of antibiotic resistance accessible to pathogens. Due to the high likelihood of contact and genetic exchange with pathogens during disease progression, the human microflora warrants special attention as perhaps the most accessible reservoir of resistance genes. Indeed, numerous previous studies have demonstrated substantial antibiotic resistance in cultured isolates from the human microflora. By applying metagenomic functional selections, we recently demonstrated that the functional repertoire of resistance genes in the human microbiome is much more diverse than suggested using previous culture-dependent methods. We showed that many resistance genes from cultured proteobacteria from human fecal samples are identical to resistance genes harbored by human pathogens, providing strong support for recent genetic exchange of this resistance machinery. In contrast, most of the resistance genes we identified with culture independent metagenomic sampling from the same samples were novel when compared to all known genes in public databases. While this clearly demonstrates that the antibiotic resistance reservoir of the large fraction of the human microbiome recalcitrant to culturing is severely under sampled, it may also suggest that barriers exist to lateral gene transfer between these bacteria and readily cultured human pathogens. If we hope to turn the tide against multidrug resistant infections, we must urgently commit to quantitatively characterizing the resistance reservoirs encoded by our diverse human microbiomes, with a particular focus on routes of exchange of these reservoirs with other microbial communities. | 2010 | 21178459 |
| 4263 | 16 | 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 |
| 4262 | 17 | 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 |
| 4265 | 18 | 0.9999 | Bacteriophages as vehicles of the resistome in cystic fibrosis. Environmental microbial communities and human microbiota represent a huge reservoir of mobilizable genes, the 'mobilome', including a pool of genes encoding antimicrobial resistance, the 'resistome'. Whole-genome sequencing of bacterial genomes from cystic fibrosis (CF) patients has demonstrated that bacteriophages contribute significantly to bacterial genome alterations, and metagenomic analysis of respiratory tract DNA viral communities has revealed the presence of genes encoding antimicrobial resistance in bacteriophages of CF patients. CF airways should now be considered as the site of complex microbiota, where bacteriophages are vehicles for the adaptation of bacteria to this specific environment and for the emergence and selection of multidrug-resistant bacteria with chimeric repertoires. As phages are already known to be mobilized during chronic infection of the lungs of patients with CF, it seems particularly important to improve the understanding of the mechanisms of phage induction to prevent the spread of virulence and/or antimicrobial resistance determinants within the CF population as well as in the community. Such a modern point of view may be a seminal reflection for clinical practice in the future since current antimicrobial therapy guidelines in the context of CF may lead to the emergence of genes encoding antimicrobial resistance. | 2011 | 21816766 |
| 3836 | 19 | 0.9999 | Bacterial recombination promotes the evolution of multi-drug-resistance in functionally diverse populations. Bacterial recombination is believed to be a major factor explaining the prevalence of multi-drug-resistance (MDR) among pathogenic bacteria. Despite extensive evidence for exchange of resistance genes from retrospective sequence analyses, experimental evidence for the evolutionary benefits of bacterial recombination is scarce. We compared the evolution of MDR between populations of Acinetobacter baylyi in which we manipulated both the recombination rate and the initial diversity of strains with resistance to single drugs. In populations lacking recombination, the initial presence of multiple strains resistant to different antibiotics inhibits the evolution of MDR. However, in populations with recombination, the inhibitory effect of standing diversity is alleviated and MDR evolves rapidly. Moreover, only the presence of DNA harbouring resistance genes promotes the evolution of resistance, ruling out other proposed benefits for recombination. Together, these results provide direct evidence for the fitness benefits of bacterial recombination and show that this occurs by mitigation of functional interference between genotypes resistant to single antibiotics. Although analogous to previously described mechanisms of clonal interference among alternative beneficial mutations, our results actually highlight a different mechanism by which interactions among co-occurring strains determine the benefits of recombination for bacterial evolution. | 2012 | 22048956 |