# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 9397 | 0 | 1.0000 | Conjugation Inhibitors Effectively Prevent Plasmid Transmission in Natural Environments. Plasmid conjugation is a major route for the spread of antibiotic resistance genes. Inhibiting conjugation has been proposed as a feasible strategy to stop or delay the propagation of antibiotic resistance genes. Several compounds have been shown to be conjugation inhibitors in vitro, specifically targeting the plasmid horizontal transfer machinery. However, the in vivo efficiency and the applicability of these compounds to clinical and environmental settings remained untested. Here we show that the synthetic fatty acid 2-hexadecynoic acid (2-HDA), when used as a fish food supplement, lowers the conjugation frequency of model plasmids up to 10-fold in controlled water microcosms. When added to the food for mice, 2-HDA diminished the conjugation efficiency 50-fold in controlled plasmid transfer assays carried out in the mouse gut. These results demonstrate the in vivo efficiency of conjugation inhibitors, paving the way for their potential application in clinical and environmental settings. IMPORTANCE The spread of antibiotic resistance is considered one of the major threats for global health in the immediate future. A key reason for the speed at which antibiotic resistance spread is the ability of bacteria to share genes with each other. Antibiotic resistance genes harbored in plasmids can be easily transferred to commensal and pathogenic bacteria through a process known as bacterial conjugation. Blocking conjugation is thus a potentially useful strategy to curtail the propagation of antibiotic resistance. Conjugation inhibitors (COINS) are a series of compounds that block conjugation in vitro. Here we show that COINS efficiently block plasmid transmission in two controlled natural environments, water microcosms and the mouse gut. These observations indicate that COIN therapy can be used to prevent the spread of antibiotic resistance. | 2021 | 34425705 |
| 9259 | 1 | 0.9999 | Static recipient cells as reservoirs of antibiotic resistance during antibiotic therapy. How does taking the full course of antibiotics prevent antibiotic resistant bacteria establishing in patients? We address this question by testing the possibility that horizontal/lateral gene transfer (HGT) is critical for the accumulation of the antibiotic-resistance phenotype while bacteria are under antibiotic stress. Most antibiotics prevent bacterial reproduction, some by preventing de novo gene expression. Nevertheless, in some cases and at some concentrations, the effects of most antibiotics on gene expression may not be irreversible. If the stress is removed before the bacteria are cleared from the patients by normal turnover, gene expression restarts, converting the residual population to phenotypic resistance. Using mathematical models we investigate how static recipients of resistance genes carried by plasmids accumulate resistance genes, and how specifically an environment cycling between presence and absence of the antibiotic uniquely favors the evolution of horizontally mobile resistance genes. We found that the presence of static recipients can substantially increase the persistence of the plasmid and that this effect is most pronounced when the cost of carriage of the plasmid decreases the cell's growth rate by as much as a half or more. In addition, plasmid persistence can be enhanced even when conjugation rates are as low as half the rate required for the plasmid to persist as a parasite on its own. | 2006 | 16723146 |
| 9697 | 2 | 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 |
| 9260 | 3 | 0.9998 | The Evolution of Plasmid Transfer Rate in Bacteria and Its Effect on Plasmid Persistence. AbstractPlasmids are extrachromosomal segments of DNA that can transfer genes between bacterial cells. Many plasmid genes benefit bacteria but cause harm to human health by granting antibiotic resistance to pathogens. Transfer rate is a key parameter for predicting plasmid dynamics, but observed rates are highly variable, and the effects of selective forces on their evolution are unclear. We apply evolutionary analysis to plasmid conjugation models to investigate selective pressures affecting plasmid transfer rate, emphasizing host versus plasmid control, the costs of plasmid transfer, and the role of recipient cells. Our analyses show that plasmid-determined transfer rates can be predicted with three parameters (host growth rate, plasmid loss rate, and the cost of plasmid transfer on growth) under some conditions. We also show that low-frequency genetic variation in transfer rate can accumulate, facilitating rapid adaptation to changing conditions. Furthermore, reduced transfer rates due to host control have limited effects on plasmid prevalence until low enough to prevent plasmid persistence. These results provide a framework to predict plasmid transfer rate evolution in different environments and demonstrate the limited impact of host mechanisms to control the costs incurred when plasmids are present. | 2021 | 34559608 |
| 9396 | 4 | 0.9998 | A CRISPR-Cas9 system protecting E. coli against acquisition of antibiotic resistance genes. Antimicrobial resistance (AMR) is an increasing problem worldwide, and new treatment options for bacterial infections are direly needed. Engineered probiotics show strong potential in treating or preventing bacterial infections. However, one concern with the use of live bacteria is the risk of the bacteria acquiring genes encoding for AMR or virulence factors through horizontal gene transfer (HGT), and the transformation of the probiotic into a superbug. Therefore, we developed an engineered CRISPR-Cas9 system that protects bacteria from horizontal gene transfer. We synthesized a CRISPR locus targeting eight AMR genes and cloned this with the Cas9 and transacting tracrRNA on a medium copy plasmid. We next evaluated the efficiency of the system to block HGT through transformation, transduction, and conjugation. Our results show that expression of the CRISPR-Cas9 system successfully protects E. coli MG1655 from acquiring the targeted resistance genes by transformation or transduction with 2-3 logs of protection depending on the system for transfer and the target gene. Furthermore, we show that the system blocks conjugation of a set of clinical plasmids, and that the system is also able to protect the probiotic bacterium E. coli Nissle 1917 from acquiring AMR genes. | 2025 | 39789078 |
| 3817 | 5 | 0.9998 | A host/plasmid system that is not dependent on antibiotics and antibiotic resistance genes for stable plasmid maintenance in Escherichia coli. Uneven distribution of plasmid-based expression vectors to daughter cells during bacterial cell division results in an increasing proportion of plasmid free cells during growth. This is a major industrial problem leading to reduction of product yields and increased production costs during large-scale cultivation of vector-carrying bacteria. For this reason, a selection must be provided that kills the plasmid free cells. The most conventional method to obtain this desired selection is to insert some gene for antibiotic resistance in the plasmid and then grow the bacteria in the presence of the corresponding antibiotic. We describe here a host/plasmid Escherichia coli system with a totally stable plasmid that can be maintained without the use of antibiotic selection. The plasmid is maintained, since it carries the small essential gene infA (coding for translation initiation factor 1, IF1) in an E. coli strain that has been deleted for its chromosomal infA gene. As a result only plasmid carrying cells can grow, making the strain totally dependent on the maintenance of the plasmid. A selection based on antibiotics is thus not necessary during cultivation, and no antibiotic-resistance genes are present neither in the final strain nor in the final plasmid. Plasmid-free cells do not accumulate even after an extended period of continuous growth. Growth rates of the control and the plasmid harboring strains are indistinguishable from each other in both LB and defined media. The indicated approach can be used to modify existing production strains and plasmids to the described concept. The infA based plasmid stability system should eliminate industrial cultivation problems caused by the loss of expression vector and use of antibiotics in the cultivation medium. Also environmental problems caused by release of antibiotics and antibiotic resistance genes, that potentially can give horizontal gene transfer between bacterial populations, are eliminated. | 2004 | 15196766 |
| 3795 | 6 | 0.9998 | Gene transfer between Salmonella enterica serovar Typhimurium inside epithelial cells. Virulence and antibiotic resistance genes transfer between bacteria by bacterial conjugation. Conjugation also mediates gene transfer from bacteria to eukaryotic organisms, including yeast and human cells. Predicting when and where genes transfer by conjugation could enhance our understanding of the risks involved in the release of genetically modified organisms, including those being developed for use as vaccines. We report here that Salmonella enterica serovar Typhimurium conjugated inside cultured human cells. The DNA transfer from donor to recipient bacteria was proportional to the probability that the two types of bacteria occupied the same cell, which was dependent on viable and invasive bacteria and on plasmid tra genes. Based on the high frequencies of gene transfer between bacteria inside human cells, we suggest that such gene transfers occur in situ. The implications of gene transfer between bacteria inside human cells, particularly in the context of antibiotic resistance, are discussed. | 2002 | 11914355 |
| 9264 | 7 | 0.9998 | Nanoalumina promotes the horizontal transfer of multiresistance genes mediated by plasmids across genera. Antibiotic resistance is a worldwide public health concern. Conjugative transfer between closely related strains or species of bacteria is an important method for the horizontal transfer of multidrug-resistance genes. The extent to which nanomaterials are able to cause an increase in antibiotic resistance by the regulation of the conjugative transfer of antibiotic-resistance genes in bacteria, especially across genera, is still unknown. Here we show that nanomaterials in water can significantly promote the horizontal conjugative transfer of multidrug-resistance genes mediated by the RP4, RK2, and pCF10 plasmids. Nanoalumina can promote the conjugative transfer of the RP4 plasmid from Escherichia coli to Salmonella spp. by up to 200-fold compared with untreated cells. We also explored the mechanisms behind this phenomenon and demonstrate that nanoalumina is able to induce oxidative stress, damage bacterial cell membranes, enhance the expression of mating pair formation genes and DNA transfer and replication genes, and depress the expression of global regulatory genes that regulate the conjugative transfer of RP4. These findings are important in assessing the risk of nanomaterials to the environment, particularly from water and wastewater treatment systems, and in the estimation of the effect of manufacture and use of nanomaterials on the environment. | 2012 | 22411796 |
| 9696 | 8 | 0.9998 | 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 |
| 9245 | 9 | 0.9998 | Type IV Coupling Proteins as Potential Targets to Control the Dissemination of Antibiotic Resistance. The increase of infections caused by multidrug-resistant bacteria, together with the loss of effectiveness of currently available antibiotics, represents one of the most serious threats to public health worldwide. The loss of human lives and the economic costs associated to the problem of the dissemination of antibiotic resistance require immediate action. Bacteria, known by their great genetic plasticity, are capable not only of mutating their genes to adapt to disturbances and environmental changes but also of acquiring new genes that allow them to survive in hostile environments, such as in the presence of antibiotics. One of the major mechanisms responsible for the horizontal acquisition of new genes (e.g., antibiotic resistance genes) is bacterial conjugation, a process mediated by mobile genetic elements such as conjugative plasmids and integrative conjugative elements. Conjugative plasmids harboring antibiotic resistance genes can be transferred from a donor to a recipient bacterium in a process that requires physical contact. After conjugation, the recipient bacterium not only harbors the antibiotic resistance genes but it can also transfer the acquired plasmid to other bacteria, thus contributing to the spread of antibiotic resistance. Conjugative plasmids have genes that encode all the proteins necessary for the conjugation to take place, such as the type IV coupling proteins (T4CPs) present in all conjugative plasmids. Type VI coupling proteins constitute a heterogeneous family of hexameric ATPases that use energy from the ATP hydrolysis for plasmid transfer. Taking into account their essential role in bacterial conjugation, T4CPs are attractive targets for the inhibition of bacterial conjugation and, concomitantly, the limitation of antibiotic resistance dissemination. This review aims to compile present knowledge on T4CPs as a starting point for delving into their molecular structure and functioning in future studies. Likewise, the scientific literature on bacterial conjugation inhibitors has been reviewed here, in an attempt to elucidate the possibility of designing T4CP-inhibitors as a potential solution to the dissemination of multidrug-resistant bacteria. | 2020 | 32903459 |
| 9434 | 10 | 0.9998 | 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 |
| 9684 | 11 | 0.9998 | Pesticide degrading natural multidrug resistance bacterial flora. Multidrug-resistant (MDR) bacteria are a growing threat to humans across the world. Antibiotic resistance is a global problem that has developed through continuous antibiotic use, combinatorial antibiotic use, pesticide-antibiotic cross-resistance, and horizontal gene transfer, as well as various other modes. Pesticide-antibiotic cross-resistance and the subsequent expansion of drug-resistant bacteria are critically documented in this review, the primary focus of which is to assess the impact of indiscriminate pesticide use on the development of microbial communities with parallel pesticide and multidrug resistance. The consumption of pesticide-contaminated food products and the use of broad-spectrum antibiotics by humans and in livestock animals have favored the development of both antibiotic and pesticide-resistant bacterial flora via natural selection. Pesticide resistance mainly develops through defensive bacterial adaptations such as biofilm formation, induced mutations, and horizontal/vertical gene transfer through plasmids or transposons, as well as through the increased expression of certain hydrolytic enzymes. Pesticide resistance genes are always transferred as gene clusters, and they may also carry genes essential for antibiotic resistance. Moreover, for some induced mutations, the mutated active site of the affected enzyme may allow degradation of both pesticides and antibiotics, resulting in cross-resistance. A few studies have shown that the sub-lethal exposure of wild-type strains to herbicides induces antibiotic resistance. This review concludes that xenobiotic exposure leads to cross-resistance in wild microbial flora, which requires further study to develop therapeutic approaches to overcome the threats of MDR bacteria and superbugs. | 2018 | 29223450 |
| 3816 | 12 | 0.9998 | Persistence and reversal of plasmid-mediated antibiotic resistance. In the absence of antibiotic-mediated selection, sensitive bacteria are expected to displace their resistant counterparts if resistance genes are costly. However, many resistance genes persist for long periods in the absence of antibiotics. Horizontal gene transfer (primarily conjugation) could explain this persistence, but it has been suggested that very high conjugation rates would be required. Here, we show that common conjugal plasmids, even when costly, are indeed transferred at sufficiently high rates to be maintained in the absence of antibiotics in Escherichia coli. The notion is applicable to nine plasmids from six major incompatibility groups and mixed populations carrying multiple plasmids. These results suggest that reducing antibiotic use alone is likely insufficient for reversing resistance. Therefore, combining conjugation inhibition and promoting plasmid loss would be an effective strategy to limit conjugation-assisted persistence of antibiotic resistance. | 2017 | 29162798 |
| 9677 | 13 | 0.9998 | Inhibiting conjugation as a tool in the fight against antibiotic resistance. Antibiotic resistance, especially in gram-negative bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid-encoded conjugation system and the host-encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addition to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics. | 2019 | 30343487 |
| 3797 | 14 | 0.9998 | Human intestinal cells modulate conjugational transfer of multidrug resistance plasmids between clinical Escherichia coli isolates. Bacterial conjugation in the human gut microbiota is believed to play a major role in the dissemination of antibiotic resistance genes and virulence plasmids. However, the modulation of bacterial conjugation by the human host remains poorly understood and there is a need for controlled systems to study this process. We established an in vitro co-culture system to study the interaction between human intestinal cells and bacteria. We show that the conjugation efficiency of a plasmid encoding an extended spectrum beta-lactamase is reduced when clinical isolates of Escherichia coli are co-cultured with human intestinal cells. We show that filtered media from co-cultures contain a factor that reduces conjugation efficiency. Protease treatment of the filtered media eliminates this inhibition of conjugation. This data suggests that a peptide or protein based factor is secreted on the apical side of the intestinal cells exposed to bacteria leading to a two-fold reduction in conjugation efficiency. These results show that human gut epithelial cells can modulate bacterial conjugation and may have relevance to gene exchange in the gut. | 2014 | 24955767 |
| 9263 | 15 | 0.9998 | The F-pilus biomechanical adaptability accelerates conjugative dissemination of antimicrobial resistance and biofilm formation. Conjugation is used by bacteria to propagate antimicrobial resistance (AMR) in the environment. Central to this process are widespread conjugative F-pili that establish the connection between donor and recipient cells, thereby facilitating the spread of IncF plasmids among enteropathogenic bacteria. Here, we show that the F-pilus is highly flexible but robust at the same time, properties that increase its resistance to thermochemical and mechanical stresses. By a combination of biophysical and molecular dynamics methods, we establish that the presence of phosphatidylglycerol molecules in the F-pilus contributes to the structural stability of the polymer. Moreover, this structural stability is important for successful delivery of DNA during conjugation and facilitates rapid formation of biofilms in harsh environmental conditions. Thus, our work highlights the importance of F-pilus structural adaptations for the efficient spread of AMR genes in a bacterial population and for the formation of biofilms that protect against the action of antibiotics. | 2023 | 37019921 |
| 9435 | 16 | 0.9998 | 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 |
| 3826 | 17 | 0.9998 | 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 |
| 3835 | 18 | 0.9998 | Plasmid-mediated phenotypic noise leads to transient antibiotic resistance in bacteria. The rise of antibiotic resistance is a critical public health concern, requiring an understanding of mechanisms that enable bacteria to tolerate antimicrobial agents. Bacteria use diverse strategies, including the amplification of drug-resistance genes. In this paper, we showed that multicopy plasmids, often carrying antibiotic resistance genes in clinical bacteria, can rapidly amplify genes, leading to plasmid-mediated phenotypic noise and transient antibiotic resistance. By combining stochastic simulations of a computational model with high-throughput single-cell measurements of bla(TEM-1) expression in Escherichia coli MG1655, we showed that plasmid copy number variability stably maintains populations composed of cells with both low and high plasmid copy numbers. This diversity in plasmid copy number enhances the probability of bacterial survival in the presence of antibiotics, while also rapidly reducing the burden of carrying multiple plasmids in drug-free environments. Our results further support the tenet that multicopy plasmids not only act as vehicles for the horizontal transfer of genetic information between cells but also as drivers of bacterial adaptation, enabling rapid modulation of gene copy numbers. Understanding the role of multicopy plasmids in antibiotic resistance is critical, and our study provides insights into how bacteria can transiently survive lethal concentrations of antibiotics. | 2024 | 38521779 |
| 3827 | 19 | 0.9998 | The fitness cost of horizontally transferred and mutational antimicrobial resistance in Escherichia coli. Antimicrobial resistance (AMR) in bacteria implies a tradeoff between the benefit of resistance under antimicrobial selection pressure and the incurred fitness cost in the absence of antimicrobials. The fitness cost of a resistance determinant is expected to depend on its genetic support, such as a chromosomal mutation or a plasmid acquisition, and on its impact on cell metabolism, such as an alteration in an essential metabolic pathway or the production of a new enzyme. To provide a global picture of the factors that influence AMR fitness cost, we conducted a systematic review and meta-analysis focused on a single species, Escherichia coli. By combining results from 46 high-quality studies in a multilevel meta-analysis framework, we find that the fitness cost of AMR is smaller when provided by horizontally transferable genes such as those encoding beta-lactamases, compared to mutations in core genes such as those involved in fluoroquinolone and rifampicin resistance. We observe that the accumulation of acquired AMR genes imposes a much smaller burden on the host cell than the accumulation of AMR mutations, and we provide quantitative estimates of the additional cost of a new gene or mutation. These findings highlight that gene acquisition is more efficient than the accumulation of mutations to evolve multidrug resistance, which can contribute to the observed dominance of horizontally transferred genes in the current AMR epidemic. | 2023 | 37455716 |