Fitness cost of antibiotic susceptibility during bacterial infection. - Related Documents




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426201.0000Fitness 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.201526203082
943610.9999Phenotypic 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.201327029301
426320.9999The 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.200717184282
961130.9999Parallel evolution of Pseudomonas aeruginosa phage resistance and virulence loss in response to phage treatment in vivo and in vitro. With rising antibiotic resistance, there has been increasing interest in treating pathogenic bacteria with bacteriophages (phage therapy). One limitation of phage therapy is the ease at which bacteria can evolve resistance. Negative effects of resistance may be mitigated when resistance results in reduced bacterial growth and virulence, or when phage coevolves to overcome resistance. Resistance evolution and its consequences are contingent on the bacteria-phage combination and their environmental context, making therapeutic outcomes hard to predict. One solution might be to conduct 'in vitro evolutionary simulations' using bacteria-phage combinations from the therapeutic context. Overall, our aim was to investigate parallels between in vitro experiments and in vivo dynamics in a human participant. Evolutionary dynamics were similar, with high levels of resistance evolving quickly with limited evidence of phage evolution. Resistant bacteria-evolved in vitro and in vivo-had lower virulence. In vivo, this was linked to lower growth rates of resistant isolates, whereas in vitro phage resistant isolates evolved greater biofilm production. Population sequencing suggests resistance resulted from selection on de novo mutations rather than sorting of existing variants. These results highlight the speed at which phage resistance can evolve in vivo, and how in vitro experiments may give useful insights for clinical evolutionary outcomes.202235188102
382740.9999The 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.202337455716
943550.9999Why 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.200212354553
426460.9999Mutational 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.201830405685
429270.9999The impact of different antibiotic regimens on the emergence of antimicrobial-resistant bacteria. BACKGROUND: The emergence and ongoing spread of antimicrobial-resistant bacteria is a major public health threat. Infections caused by antimicrobial-resistant bacteria are associated with substantially higher rates of morbidity and mortality compared to infections caused by antimicrobial-susceptible bacteria. The emergence and spread of these bacteria is complex and requires incorporating numerous interrelated factors which clinical studies cannot adequately address. METHODS/PRINCIPAL FINDINGS: A model is created which incorporates several key factors contributing to the emergence and spread of resistant bacteria including the effects of the immune system, acquisition of resistance genes and antimicrobial exposure. The model identifies key strategies which would limit the emergence of antimicrobial-resistant bacterial strains. Specifically, the simulations show that early initiation of antimicrobial therapy and combination therapy with two antibiotics prevents the emergence of resistant bacteria, whereas shorter courses of therapy and sequential administration of antibiotics promote the emergence of resistant strains. CONCLUSIONS/SIGNIFICANCE: The principal findings suggest that (i) shorter lengths of antibiotic therapy and early interruption of antibiotic therapy provide an advantage for the resistant strains, (ii) combination therapy with two antibiotics prevents the emergence of resistance strains in contrast to sequential antibiotic therapy, and (iii) early initiation of antibiotics is among the most important factors preventing the emergence of resistant strains. These findings provide new insights into strategies aimed at optimizing the administration of antimicrobials for the treatment of infections and the prevention of the emergence of antimicrobial resistance.200819112501
382980.9999Associations 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.201729089428
426190.9999Recovery and Characterization of Bacteria Resisting Infection by Lytic Bacteriophage. Bacteria and bacteriophages coexist and coevolve, bacteriophages being obligatory predators exerting an evolutionary pressure on their prey. Mechanisms in action vary depending on the bacterial genomic content and on the regulation of the bacteriophage cycle. To assess the multiplicity of bacterial genes involved in resistance as well as the changes in the bacteriophage interactions with the bacteria, it is necessary to isolate and investigate large numbers of independent resistant variants. Here we describe protocols that have been applied to the study of Pseudomonas aeruginosa and four of its virulent bacteriophages belonging to the Podoviridae and Myoviridae bacteriophage families. Mutations are identified using whole genome sequencing of resistant variants. Phenotypic analyses are performed to describe the changes conferred by the mutations.201829119434
4276100.9999Phages limit the evolution of bacterial antibiotic resistance in experimental microcosms. The evolution of multi-antibiotic resistance in bacterial pathogens, often resulting from de novo mutations, is creating a public health crisis. Phages show promise for combating antibiotic-resistant bacteria, the efficacy of which, however, may also be limited by resistance evolution. Here, we suggest that phages may be used as supplements to antibiotics in treating initially sensitive bacteria to prevent resistance evolution, as phages are unaffected by most antibiotics and there should be little cross-resistance to antibiotics and phages. In vitro experiments using the bacterium Pseudomonas fluorescens, a lytic phage, and the antibiotic kanamycin supported this prediction: an antibiotic-phage combination dramatically decreased the chance of bacterial population survival that indicates resistance evolution, compared with antibiotic treatment alone, whereas the phage alone did not affect bacterial survival. This effect of the combined treatment in preventing resistance evolution was robust to immigration of bacteria from an untreated environment, but not to immigration from environment where the bacteria had coevolved with the phage. By contrast, an isogenic hypermutable strain constructed from the wild-type P. fluorescens evolved resistance to all treatments regardless of immigration, but typically suffered very large fitness costs. These results suggest that an antibiotic-phage combination may show promise as an antimicrobial strategy.201223028398
4267110.9999Relationship 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.202033092201
8999120.9999Growth-Dependent Predation and Generalized Transduction of Antimicrobial Resistance by Bacteriophage. Bacteriophage (phage) are both predators and evolutionary drivers for bacteria, notably contributing to the spread of antimicrobial resistance (AMR) genes by generalized transduction. Our current understanding of this complex relationship is limited. We used an interdisciplinary approach to quantify how these interacting dynamics can lead to the evolution of multidrug-resistant bacteria. We cocultured two strains of methicillin-resistant Staphylococcus aureus, each harboring a different antibiotic resistance gene, with generalized transducing phage. After a growth phase of 8 h, bacteria and phage surprisingly coexisted at a stable equilibrium in our culture, the level of which was dependent on the starting concentration of phage. We detected double-resistant bacteria as early as 7 h, indicating that transduction of AMR genes had occurred. We developed multiple mathematical models of the bacteria and phage relationship and found that phage-bacteria dynamics were best captured by a model in which phage burst size decreases as the bacteria population reaches stationary phase and where phage predation is frequency-dependent. We estimated that one in every 10(8) new phage generated was a transducing phage carrying an AMR gene and that double-resistant bacteria were always predominantly generated by transduction rather than by growth. Our results suggest a shift in how we understand and model phage-bacteria dynamics. Although rates of generalized transduction could be interpreted as too rare to be significant, they are sufficient in our system to consistently lead to the evolution of multidrug-resistant bacteria. Currently, the potential of phage to contribute to the growing burden of AMR is likely underestimated. IMPORTANCE Bacteriophage (phage), viruses that can infect and kill bacteria, are being investigated through phage therapy as a potential solution to the threat of antimicrobial resistance (AMR). In reality, however, phage are also natural drivers of bacterial evolution by transduction when they accidentally carry nonphage DNA between bacteria. Using laboratory work and mathematical models, we show that transduction leads to evolution of multidrug-resistant bacteria in less than 8 h and that phage production decreases when bacterial growth decreases, allowing bacteria and phage to coexist at stable equilibria. The joint dynamics of phage predation and transduction lead to complex interactions with bacteria, which must be clarified to prevent phage from contributing to the spread of AMR.202235311576
9683130.9999Antimicrobial 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.201323554414
4061140.9999Beyond serial passages: new methods for predicting the emergence of resistance to novel antibiotics. Market launching of a new antibiotic requires knowing in advance its benefits and possible risks, and among them how rapidly resistance will emerge and spread among bacterial pathogens. This information is not only useful from a public health point of view, but also for pharmaceutical industry, in order to reduce potential waste of resources in the development of a compound that might be discontinued at the short term because of resistance development. Most assays currently used for predicting the emergence of resistance are based on culturing the target bacteria by serial passages in the presence of increasing concentrations of antibiotics. Whereas these assays may be valuable for identifying mutations that might cause resistance, they are not useful to establish how fast resistance might appear, neither to address the risk of spread of resistance genes by horizontal gene transfer. In this article, we review recent information pertinent for a more accurate prediction on the emergence and dispersal of antibiotic resistance.201121835695
4271150.9999Multi-step vs. single-step resistance evolution under different drugs, pharmacokinetics, and treatment regimens. The success of antimicrobial treatment is threatened by the evolution of drug resistance. Population genetic models are an important tool in mitigating that threat. However, most such models consider resistance emergence via a single mutational step. Here, we assembled experimental evidence that drug resistance evolution follows two patterns: (i) a single mutation, which provides a large resistance benefit, or (ii) multiple mutations, each conferring a small benefit, which combine to yield high-level resistance. Using stochastic modeling, we then investigated the consequences of these two patterns for treatment failure and population diversity under various treatments. We find that resistance evolution is substantially limited if more than two mutations are required and that the extent of this limitation depends on the combination of drug type and pharmacokinetic profile. Further, if multiple mutations are necessary, adaptive treatment, which only suppresses the bacterial population, delays treatment failure due to resistance for a longer time than aggressive treatment, which aims at eradication.202134001313
4266160.9999Novel 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.202032117183
3836170.9999Bacterial 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.201222048956
4269180.9999Whole-cell modeling of E. coli colonies enables quantification of single-cell heterogeneity in antibiotic responses. Antibiotic resistance poses mounting risks to human health, as current antibiotics are losing efficacy against increasingly resistant pathogenic bacteria. Of particular concern is the emergence of multidrug-resistant strains, which has been rapid among Gram-negative bacteria such as Escherichia coli. A large body of work has established that antibiotic resistance mechanisms depend on phenotypic heterogeneity, which may be mediated by stochastic expression of antibiotic resistance genes. The link between such molecular-level expression and the population levels that result is complex and multi-scale. Therefore, to better understand antibiotic resistance, what is needed are new mechanistic models that reflect single-cell phenotypic dynamics together with population-level heterogeneity, as an integrated whole. In this work, we sought to bridge single-cell and population-scale modeling by building upon our previous experience in "whole-cell" modeling, an approach which integrates mathematical and mechanistic descriptions of biological processes to recapitulate the experimentally observed behaviors of entire cells. To extend whole-cell modeling to the "whole-colony" scale, we embedded multiple instances of a whole-cell E. coli model within a model of a dynamic spatial environment, allowing us to run large, parallelized simulations on the cloud that contained all the molecular detail of the previous whole-cell model and many interactive effects of a colony growing in a shared environment. The resulting simulations were used to explore the response of E. coli to two antibiotics with different mechanisms of action, tetracycline and ampicillin, enabling us to identify sub-generationally-expressed genes, such as the beta-lactamase ampC, which contributed greatly to dramatic cellular differences in steady-state periplasmic ampicillin and was a significant factor in determining cell survival.202337327241
9615190.9999Persistence and resistance as complementary bacterial adaptations to antibiotics. Bacterial persistence represents a simple of phenotypic heterogeneity, whereby a proportion of cells in an isogenic bacterial population can survive exposure to lethal stresses such as antibiotics. In contrast, genetically based antibiotic resistance allows for continued growth in the presence of antibiotics. It is unclear, however, whether resistance and persistence are complementary or alternative evolutionary adaptations to antibiotics. Here, we investigate the co-evolution of resistance and persistence across the genus Pseudomonas using comparative methods that correct for phylogenetic nonindependence. We find that strains of Pseudomonas vary extensively in both their intrinsic resistance to antibiotics (ciprofloxacin and rifampicin) and persistence following exposure to these antibiotics. Crucially, we find that persistence correlates positively to antibiotic resistance across strains. However, we find that different genes control resistance and persistence implying that they are independent traits. Specifically, we find that the number of type II toxin-antitoxin systems (TAs) in the genome of a strain is correlated to persistence, but not resistance. Our study shows that persistence and antibiotic resistance are complementary, but independent, evolutionary adaptations to stress and it highlights the key role played by TAs in the evolution of persistence.201626999656