The evolution of plasmid-carried antibiotic resistance (original) (raw)
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Evolutionary paths that expand plasmid host-range: implications for spread of antibiotic resistance
Molecular Biology and Evolution, 2015
The World Health Organization has declared the emergence of antibiotic resistance to be a global threat to human health. Broad-host-range plasmids have a key role in causing this health crisis because they transfer multiple resistance genes to a wide range of bacteria. To limit the spread of antibiotic resistance, we need to gain insight into the mechanisms by which the host range of plasmids evolves. Although initially unstable plasmids have been shown to improve their persistence through evolution of the plasmid, the host, or both, the means by which this occurs are poorly understood. Here, we sought to identify the underlying genetic basis of expanded plasmid host-range and increased persistence of an antibiotic resistance plasmid using a combined experimental-modeling approach that included whole-genome resequencing, molecular genetics and a plasmid population dynamics model. In nine of the ten previously evolved clones, changes in host and plasmid each slightly improved plasmid persistence, but their combination resulted in a much larger improvement, which indicated positive epistasis. The only genetic change in the plasmid was the acquisition of a transposable element from a plasmid native to the Pseudomonas host used in these studies. The analysis of genetic deletions showed that the critical genes on this transposon encode a putative toxin-antitoxin (TA) and a cointegrate resolution system. As evolved plasmids were able to persist longer in multiple na€ ıve hosts, acquisition of this transposon also expanded the plasmid's host range, which has important implications for the spread of antibiotic resistance.
Mathematical Models of Plasmid Population Dynamics
Frontiers in Microbiology, 2021
With plasmid-mediated antibiotic resistance thriving and threatening to become a serious public health problem, it is paramount to increase our understanding of the forces that enable the spread and maintenance of drug resistance genes encoded in mobile genetic elements. The relevance of plasmids as vehicles for the dissemination of antibiotic resistance genes, in addition to the extensive use of plasmid-derived vectors for biotechnological and industrial purposes, has promoted the in-depth study of the molecular mechanisms controlling multiple aspects of a plasmids’ life cycle. This body of experimental work has been paralleled by the development of a wealth of mathematical models aimed at understanding the interplay between transmission, replication, and segregation, as well as their consequences in the ecological and evolutionary dynamics of plasmid-bearing bacterial populations. In this review, we discuss theoretical models of plasmid dynamics that span from the molecular mechan...
Compensatory mutations improve general permissiveness to antibiotic resistance plasmids
Nature Ecology & Evolution, 2017
Horizontal gene transfer mediated by broad-host-range plasmids is an important mechanism of antibiotic resistance spread. While not all bacteria maintain plasmids equally well, plasmid persistence can improve over time, yet no general evolutionary mechanisms have emerged. Our goal was to identify these mechanisms, and to assess if adaptation to one plasmid affects the permissiveness to others. We experimentally evolved Pseudomonas sp. H2 containing multi-drug resistance plasmid RP4, determined plasmid persistence and cost using a joint experimentalmodeling approach, resequenced evolved clones, and reconstructed key mutations. Plasmid persistence improved in fewer than 600 generations because the fitness cost turned into a benefit. Improved retention of naive plasmids indicated that the host evolved towards increased plasmid permissiveness. Key chromosomal mutations affected two accessory helicases and the RNA Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Emerging patterns of plasmid-host coevolution that stabilize antibiotic resistance
Multidrug resistant bacterial pathogens have become a serious global human health threat, and conjugative plasmids are important drivers of the rapid spread of resistance to last-resort antibiotics. Whereas antibiotics have been shown to select for adaptation of resistance plasmids to their new bacterial hosts, or vice versa , a general evolutionary mechanism has not yet emerged. Here we conducted an experimental evolution study aimed at determining general patterns of plasmid-bacteria evolution. Specifically, we found that a large conjugative resistance plasmid follows the same evolutionary trajectories as its non-conjugative mini-replicon in the same and other species. Furthermore, within a single host-plasmid pair three distinct patterns of adaptive evolution led to increased plasmid persistence: i) mutations in the replication protein gene ( trfA1 ); ii) the acquisition by the resistance plasmid of a transposon from a co-residing plasmid encoding a putative toxin-antitoxin syste...
Plasmid, 2014
Antibiotic resistance increases costs for health care and causes therapy failure. An important mechanism for spreading resistance is transfer of plasmids containing resistance genes and subsequent selection. Yet the factors that influence the rate of transfer are poorly known. Rates of plasmid transfer were measured in co-cultures in chemostats of a donor and a acceptor strain under various selective pressures. To document whether specific mutations in either plasmid or acceptor genome are associated with the plasmid transfer, whole genome sequencing was performed. The DM0133 TetR tetracycline resistance plasmid was transferred between Escherichia coli K-12 strains during co-culture at frequencies that seemed higher at increased growth rate. Modeling of the take-over of the culture by the transformed strain suggests that in reality more transfer events occurred at low growth rates. At moderate selection pressure due to an antibiotic concentration that still allowed growth, a maximum transfer frequency was determined of once per 10 11 cell divisions. In the absence of tetracycline or in the presence of high concentrations the frequency of transfer was sometimes zero, but otherwise reduced by at least a factor of 5. Whole genome sequencing showed that the plasmid was transferred without mutations, but two functional mutations in the genome of the recipient strain accompanied this transfer. Exposure to concentrations of antibiotics that fall within the mutant selection window stimulated transfer of the resistance plasmid most.
Applied Mathematical Modelling, 2019
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights • We model the interaction between sensitive and resistant bacteria to an antibiotic. • Qualitative analysis reveals the existence of a hopf bifurcation around the endemic equilibrium where both bacteria coexist. • We consider the most basic mechanisms of acquisition of bacterial resistance to antibiotics (mutations and plasmids) • Conditions that determine outcome of bacterial elimination or progression are established.
Natural Selection, Infectious Transfer and the Existence Conditions for Bacterial Plasmids
Genetics, 2000
Despite the near-ubiquity of plasmids in bacterial populations and the profound contribution of infectious gene transfer to the adaptation and evolution of bacteria, the mechanisms responsible for the maintenance of plasmids in bacterial populations are poorly understood. In this article, we address the question of how plasmids manage to persist over evolutionary time. Empirical studies suggest that plasmids are not infectiously transmitted at a rate high enough to be maintained as genetic parasites. In part i, we present a general mathematical proof that if this is the case, then plasmids will not be able to persist indefinitely solely by carrying genes that are beneficial or sometimes beneficial to their host bacteria. Instead, such genes should, in the long run, be incorporated into the bacterial chromosome. If the mobility of host-adaptive genes imposes a cost, that mobility will eventually be lost. In part ii, we illustrate a pair of mechanisms by which plasmids can be maintain...
Evolutionary Applications, 2013
The emergence of pathogenic bacteria resistant to multiple antibiotics is a serious worldwide public health concern. Whenever antibiotics are applied, the genes encoding for antibiotic resistance are selected for within bacterial populations. This has led to the prevalence of conjugative plasmids that carry resistance genes and can transfer themselves between diverse bacterial groups. In this study, we investigated whether it is feasible to attempt to prevent the spread of antibiotic resistances with a lytic bacteriophage, which can replicate in a wide range of gram-negative bacteria harbouring conjugative drug resistance-conferring plasmids. The counter-selection against the plasmid was shown to be effective, reducing the frequency of multidrug-resistant bacteria that formed via horizontal transfer by several orders of magnitude. This was true also in the presence of an antibiotic against which the plasmid provided resistance. Majority of the multiresistant bacteria subjected to phage selection also lost their conjugation capability. Overall this study suggests that, while we are obligated to maintain the selection for the spread of the drug resistances, the 'fight evolution with evolution' approach could help us even out the outcome to our favour.
Modeling the evolutionary dynamics of plasmids in spatial populations
Proceedings of the 13th annual conference on Genetic and evolutionary computation - GECCO '11, 2011
One of the processes by which microorganisms are able to rapidly adapt to changing conditions is horizontal gene transfer, whereby an organism incorporates additional genetic material from sources other than its parent. These genetic elements may encode a wide variety of beneficial traits. Under certain conditions, many computational models capture the evolutionary dynamics of adaptive behaviors such as toxin production, quorum sensing, and biofilm formation, and have even provided new insights into otherwise unknown or misunderstood phenomena. However, such models rarely incorporate horizontal gene transfer, so they may be incapable of fully representing the vast repertoire of behaviors exhibited by natural populations. Although models of horizontal gene transfer exist, they rarely account for the spatial structure of populations, which is often critical to adaptive behaviors. In this work we develop a spatial model to examine how conjugation, one mechanism of horizontal gene transfer, can be maintained in populations. We investigate how both the costs of transfer and the benefits conferred affect evolutionary outcomes. Further, we examine how rates of transmission evolve, allowing this system to adapt to different environments. Through spatial models such as these, we can gain a greater understanding of the conditions under which horizontally-acquired behaviors are evolved and are maintained.