Compensatory evolution of chromosomes and plasmids counteracts the plasmid fitness cost. - Related Documents




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924201.0000Compensatory evolution of chromosomes and plasmids counteracts the plasmid fitness cost. Plasmids incur a fitness cost that has the potential to restrict the dissemination of resistance in bacterial pathogens. However, bacteria can overcome this disadvantage by compensatory evolution to maintain their resistance. Compensatory evolution can occur via both chromosomes and plasmids, but there are a few reviews regarding this topic, and most of them focus on plasmids. In this review, we provide a comprehensive overview of the currently reported mechanisms underlying compensatory evolution on chromosomes and plasmids, elucidate key targets regulating plasmid fitness cost, and discuss future challenges in this field. We found that compensatory evolution on chromosomes primarily arises from mutations in transcriptional regulatory factors, whereas compensatory evolution of plasmids predominantly involves three pathways: plasmid copy number regulation, conjugation transfer efficiency, and expression of antimicrobial resistance (AMR) genes. Furthermore, the importance of reasonable selection of research subjects and effective integration of diverse advanced research methods is also emphasized in our future study on compensatory mechanisms. Overall, this review establishes a theoretical framework that aims to provide innovative ideas for minimizing the emergence and spread of AMR genes.202439170056
949410.9999Within-Host Mathematical Models of Antibiotic Resistance. Mathematical models have been used to study the spread of infectious diseases from person to person. More recently studies are developing within-host modeling which provides an understanding of how pathogens-bacteria, fungi, parasites, or viruses-develop, spread, and evolve inside a single individual and their interaction with the host's immune system.Such models have the potential to provide a more detailed and complete description of the pathogenesis of diseases within-host and identify other influencing factors that may not be detected otherwise. Mathematical models can be used to aid understanding of the global antibiotic resistance (ABR) crisis and identify new ways of combating this threat.ABR occurs when bacteria respond to random or selective pressures and adapt to new environments through the acquisition of new genetic traits. This is usually through the acquisition of a piece of DNA from other bacteria, a process called horizontal gene transfer (HGT), the modification of a piece of DNA within a bacterium, or through. Bacteria have evolved mechanisms that enable them to respond to environmental threats by mutation, and horizontal gene transfer (HGT): conjugation; transduction; and transformation. A frequent mechanism of HGT responsible for spreading antibiotic resistance on the global scale is conjugation, as it allows the direct transfer of mobile genetic elements (MGEs). Although there are several MGEs, the most important MGEs which promote the development and rapid spread of antimicrobial resistance genes in bacterial populations are plasmids and transposons. Each of the resistance-spread-mechanisms mentioned above can be modeled allowing us to understand the process better and to define strategies to reduce resistance.202438949703
949320.9999Regulatory integration of horizontally-transferred genes in bacteria. Horizontal transfer of genetic material is a fact of microbial life and bacteria can obtain new DNA sequences through the processes of conjugation, transduction and transformation. This offers the bacterium the possibility of evolving rapidly by importing new genes that code for new traits that may assist in environmental adaptation. Research in this area has focused in particular on the role of horizontal transfer in the dissemination through bacterial populations of genes for resistance to antimicrobial agents, including antibiotics. It is becoming clear that many other phenotypic characteristics have been acquired through horizontal routes and that these include traits contributing to pathogenesis and symbiosis. An important corollary to the acquisition of new genes is the problem of how best to integrate them in the existing gene regulatory circuits of the recipient so that fitness is not compromised initially and can be enhanced in the future through optimal expression of the new genes.200919273337
948530.9998Evolution of Drug Resistance in Bacteria. Resistance to antibiotics is an important and timely problem of contemporary medicine. Rapid evolution of resistant bacteria calls for new preventive measures to slow down this process, and a longer-term progress cannot be achieved without a good understanding of the mechanisms through which drug resistance is acquired and spreads in microbial populations. Here, we discuss recent experimental and theoretical advances in our knowledge how the dynamics of microbial populations affects the evolution of antibiotic resistance . We focus on the role of spatial and temporal drug gradients and show that in certain situations bacteria can evolve de novo resistance within hours. We identify factors that lead to such rapid onset of resistance and discuss their relevance for bacterial infections.201627193537
949040.9998The superbugs: evolution, dissemination and fitness. Since the introduction of antibiotics, bacteria have not only evolved elegant resistance mechanisms to thwart their effect, but have also evolved ways in which to disseminate themselves or their resistance genes to other susceptible bacteria. During the past few years, research has revealed not only how such resistance mechanisms have been able to evolve and to rapidly disseminate, but also how bacteria have, in some cases, been able to adapt to this new burden of resistance with little or no cost to their fitness. Such adaptations make the control of these superbugs all the more difficult.199810066531
924150.9998Evolutionary Mechanisms Shaping the Maintenance of Antibiotic Resistance. Antibiotics target essential cellular functions but bacteria can become resistant by acquiring either exogenous resistance genes or chromosomal mutations. Resistance mutations typically occur in genes encoding essential functions; these mutations are therefore generally detrimental in the absence of drugs. However, bacteria can reduce this handicap by acquiring additional mutations, known as compensatory mutations. Genetic interactions (epistasis) either with the background or between resistances (in multiresistant bacteria) dramatically affect the fitness cost of antibiotic resistance and its compensation, therefore shaping dissemination of antibiotic resistance mutations. This Review summarizes current knowledge on the evolutionary mechanisms influencing maintenance of resistance mediated by chromosomal mutations, focusing on their fitness cost, compensatory evolution, epistasis, and the effect of the environment on these processes.201829439838
947260.9998Bacteriophage and Bacterial Susceptibility, Resistance, and Tolerance to Antibiotics. Bacteriophages, viruses that infect and replicate within bacteria, impact bacterial responses to antibiotics in complex ways. Recent studies using lytic bacteriophages to treat bacterial infections (phage therapy) demonstrate that phages can promote susceptibility to chemical antibiotics and that phage/antibiotic synergy is possible. However, both lytic and lysogenic bacteriophages can contribute to antimicrobial resistance. In particular, some phages mediate the horizontal transfer of antibiotic resistance genes between bacteria via transduction and other mechanisms. In addition, chronic infection filamentous phages can promote antimicrobial tolerance, the ability of bacteria to persist in the face of antibiotics. In particular, filamentous phages serve as structural elements in bacterial biofilms and prevent the penetration of antibiotics. Over time, these contributions to antibiotic tolerance favor the selection of resistance clones. Here, we review recent insights into bacteriophage contributions to antibiotic susceptibility, resistance, and tolerance. We discuss the mechanisms involved in these effects and address their impact on bacterial fitness.202235890320
948370.9998Ecological and evolutionary mechanisms driving within-patient emergence of antimicrobial resistance. The ecological and evolutionary mechanisms of antimicrobial resistance (AMR) emergence within patients and how these vary across bacterial infections are poorly understood. Increasingly widespread use of pathogen genome sequencing in the clinic enables a deeper understanding of these processes. In this Review, we explore the clinical evidence to support four major mechanisms of within-patient AMR emergence in bacteria: spontaneous resistance mutations; in situ horizontal gene transfer of resistance genes; selection of pre-existing resistance; and immigration of resistant lineages. Within-patient AMR emergence occurs across a wide range of host niches and bacterial species, but the importance of each mechanism varies between bacterial species and infection sites within the body. We identify potential drivers of such differences and discuss how ecological and evolutionary analysis could be embedded within clinical trials of antimicrobials, which are powerful but underused tools for understanding why these mechanisms vary between pathogens, infections and individuals. Ultimately, improving understanding of how host niche, bacterial species and antibiotic mode of action combine to govern the ecological and evolutionary mechanism of AMR emergence in patients will enable more predictive and personalized diagnosis and antimicrobial therapies.202438689039
948480.9998Phage-antibiotic combinations: a promising approach to constrain resistance evolution in bacteria. Antibiotic resistance has reached dangerously high levels throughout the world. A growing number of bacteria pose an urgent, serious, and concerning threat to public health. Few new antibiotics are available to clinicians and only few are in development, highlighting the need for new strategies to overcome the antibiotic resistance crisis. Combining existing antibiotics with phages, viruses the infect bacteria, is an attractive and promising alternative to standalone therapies. Phage-antibiotic combinations have been shown to suppress the emergence of resistance in bacteria, and sometimes even reverse it. Here, we discuss the mechanisms by which phage-antibiotic combinations reduce resistance evolution, and the potential limitations these mechanisms have in steering microbial resistance evolution in a desirable direction. We also emphasize the importance of gaining a better understanding of mechanisms behind physiological and evolutionary phage-antibiotic interactions in complex in-patient environments.202133175408
948190.9998Genetic linkage and horizontal gene transfer, the roots of the antibiotic multi-resistance problem. Bacteria carrying resistance genes for many antibiotics are moving beyond the clinic into the community, infecting otherwise healthy people with untreatable and frequently fatal infections. This state of affairs makes it increasingly important that we understand the sources of this problem in terms of bacterial biology and ecology and also that we find some new targets for drugs that will help control this growing epidemic. This brief and eclectic review takes the perspective that we have too long thought about the problem in terms of treatment with or resistance to a single antibiotic at a time, assuming that dissemination of the resistance gene was affected by simple vertical inheritance. In reality antibiotic resistance genes are readily transferred horizontally, even to and from distantly related bacteria. The common agents of bacterial gene transfer are described and also one of the processes whereby nonantibiotic chemicals, specifically toxic metals, in the environment can select for and enrich bacteria with antibiotic multiresistance. Lastly, some speculation is offered on broadening our perspective on this problem to include drugs directed at compromising the ability of the mobile elements themselves to replicate, transfer, and recombine, that is, the three "infrastructure" processes central to the movement of genes among bacteria.200617127524
9492100.9998The Search for 'Evolution-Proof' Antibiotics. The effectiveness of antibiotics has been widely compromised by the evolution of resistance among pathogenic bacteria. It would be restored by the development of antibiotics to which bacteria cannot evolve resistance. We first discuss two kinds of 'evolution-proof' antibiotic. The first comprises literally evolution-proof antibiotics to which bacteria cannot become resistant by mutation or horizontal gene transfer. The second category comprises agents to which resistance may arise, but so rarely that it does not become epidemic. The likelihood that resistance to a novel agent will spread is evaluated here by a simple model that includes biological and therapeutic parameters governing the evolution of resistance within hosts and the transmission of resistant strains between hosts. This model leads to the conclusion that epidemic spread is unlikely if the frequency of mutations that confer resistance falls below a defined minimum value, and it identifies potential targets for intervention to prevent the evolution of resistance. Whether or not evolution-proof antibiotics are ever found, searching for them is likely to improve the deployment of new and existing agents by advancing our understanding of how resistance evolves.201829191398
9486110.9998Acquired Bacterial Resistance to Antibiotics and Resistance Genes: From Past to Future. The discovery, commercialization, and regular administration of antimicrobial agents have revolutionized the therapeutic paradigm, making it possible to treat previously untreatable and fatal infections. However, the excessive use of antibiotics has led to develop resistance soon after their use in clinical practice, to the point of becoming a global emergency. The mechanisms of bacterial resistance to antibiotics are manifold, including mechanisms of destruction or inactivation, target site modification, or active efflux, and represent the main examples of evolutionary adaptation for the survival of bacterial species. The acquirement of new resistance mechanisms is a consequence of the great genetic plasticity of bacteria, which triggers specific responses that result in mutational adaptation, acquisition of genetic material, or alteration of gene expression, virtually producing resistance to all currently available antibiotics. Understanding resistance processes is critical to the development of new antimicrobial agents to counteract drug-resistant microorganisms. In this review, both the mechanisms of action of antibiotic resistance (AMR) and the antibiotic resistance genes (ARGs) mainly found in clinical and environmental bacteria will be reviewed. Furthermore, the evolutionary background of multidrug-resistant bacteria will be examined, and some promising elements to control or reduce the emergence and spread of AMR will be proposed.202540149034
9585120.9998When Humans Met Superbugs: Strategies to Tackle Bacterial Resistances to Antibiotics. Bacterial resistance to antibiotics poses enormous health and economic burdens to our society, and it is of the essence to explore old and new ways to deal with these problems. Here we review the current status of multi-resistance genes and how they spread among bacteria. We discuss strategies to deal with resistant bacteria, namely the search for new targets and the use of inhibitors of protein-protein interactions, fragment-based methods, or modified antisense RNAs. Finally, we discuss integrated approaches that consider bacterial populations and their niches, as well as the role of global regulators that activate and/or repress the expression of multiple genes in fluctuating environments and, therefore, enable resistant bacteria to colonize new niches. Understanding how the global regulatory circuits work is, probably, the best way to tackle bacterial resistance.201830811343
9188130.9998CRISPR-Cas system, antibiotic resistance and virulence in bacteria: Through a common lens. CRISPR-Cas system, antibiotic resistance and virulence are different modes of survival for the bacteria. CRISPR-Cas is an adaptive immune system that can degrade foreign DNA, antibiotic resistance helps bacteria to evade drugs that can threaten their existence and virulence determinants are offensive tools that can facilitate the establishment of infection by pathogens. This chapter focuses on these three aspects, providing insights about the CRISPR system and resistance mechanisms in brief, followed by understanding the synergistic or antagonistic relationship of resistance and virulence determinants in connection to the CRISPR system. We have addressed the discussion of this evolving topic through specific examples and studies. Different approaches for successful detection of this unique defense system in bacteria and various applications of the CRISPR-Cas systems to show how it can be harnessed to tackle the increasing problem of antibiotic resistance have been put forth. World Health Organization has declared antibiotic resistance as a serious global problem of the 21st century. As antibiotic-resistant bacteria increase their footprint across the globe, newer tools such as the CRISPR-Cas system hold immense promise to tackle this problem.202133685595
9533140.9998The disparate effects of bacteriophages on antibiotic-resistant bacteria. Faced with the crisis of multidrug-resistant bacteria, bacteriophages, viruses that infect and replicate within bacteria, have been reported to have both beneficial and detrimental effects with respect to disease management. Bacteriophages (phages) have important ecological and evolutionary impacts on their bacterial hosts and have been associated with therapeutic use to kill bacterial pathogens, but can lead to the transmission of antibiotic resistance. Although the process known as transduction has been reported for many bacterial species by classic and modern genetic approaches, its contribution to the spread of antibiotic resistance in nature remains unclear. In addition, detailed molecular studies have identified phages residing in bacterial genomes, revealing unexpected interactions between phages and their bacterial hosts. Importantly, antibiotics can induce the production of phages and phage-encoded products, disseminating these viruses and virulence-related genes, which have dangerous consequences for disease severity. These unwanted side-effects of antibiotics cast doubt on the suitability of some antimicrobial treatments and may require new strategies to prevent and limit the selection for virulence. Foremost among these treatments is phage therapy, which could be used to treat many bacterial infectious diseases and confront the pressing problem of antibiotic resistance in pathogenic bacteria. This review discusses the interactions between bacteriophages, antibiotics, and bacteria and provides an integrated perspective that aims to inspire the development of successful antibacterial therapies.201830302018
9673150.9998Evolution of Plasmid-Mediated Antibiotic Resistance in the Clinical Context. Antibiotic-resistant infections are an urgent problem in clinical settings because they sharply increase mortality risk in critically ill patients. The horizontal spread of antibiotic resistance genes among bacteria is driven by bacterial plasmids, promoting the evolution of resistance. Crucially, particular associations exist between resistance plasmids and bacterial clones that become especially successful in clinical settings. However, the factors underlying the success of these associations remain unknown. Recent in vitro evidence reveals (i) that plasmids produce fitness costs in bacteria, and (ii) that these costs are alleviated over time through compensatory mutations. I argue that plasmid-imposed costs and subsequent compensatory adaptation may determine the success of associations between plasmids and bacteria in clinical settings, shaping the in vivo evolution of antibiotic resistance.201830049587
9534160.9998Defining the Benefits of Antibiotic Resistance in Commensals and the Scope for Resistance Optimization. Antibiotic resistance is a major medical and public health challenge, characterized by global increases in the prevalence of resistant strains. The conventional view is that all antibiotic resistance is problematic, even when not in pathogens. Resistance in commensal bacteria poses risks, as resistant organisms can provide a reservoir of resistance genes that can be horizontally transferred to pathogens or may themselves cause opportunistic infections in the future. While these risks are real, we propose that commensal resistance can also generate benefits during antibiotic treatment of human infection, by promoting continued ecological suppression of pathogens. To define and illustrate this alternative conceptual perspective, we use a two-species mathematical model to identify the necessary and sufficient ecological conditions for beneficial resistance. We show that the benefits are limited to species (or strain) interactions where commensals suppress pathogen growth and are maximized when commensals compete with, rather than prey on or otherwise exploit pathogens. By identifying benefits of commensal resistance, we propose that rather than strictly minimizing all resistance, resistance management may be better viewed as an optimization problem. We discuss implications in two applied contexts: bystander (nontarget) selection within commensal microbiomes and pathogen treatment given polymicrobial infections. IMPORTANCE Antibiotic resistance is commonly viewed as universally costly, regardless of which bacterial cells express resistance. Here, we derive an opposing logic, where resistance in commensal bacteria can lead to reductions in pathogen density and improved outcomes on both the patient and public health scales. We use a mathematical model of commensal-pathogen interactions to define the necessary and sufficient conditions for beneficial resistance, highlighting the importance of reciprocal ecological inhibition to maximize the benefits of resistance. More broadly, we argue that determining the benefits as well as the costs of resistances in human microbiomes can transform resistance management from a minimization to an optimization problem. We discuss applied contexts and close with a review of key resistance optimization dimensions, including the magnitude, spectrum, and mechanism of resistance.202336475750
9720170.9998Molecular Evolution and Origins of Antibiotic Resistance Genes. Antibiotic resistance is a global health crisis with bacteria resisting both natural and synthetic antibiotics. While all antibiotic classes face similar mechanistic and evolutionary forces, their origins shape distinct resistance pathways. Produced over millions of years, natural antibiotics drove the early emergence and coevolution of antibiotic resistance genes (ARGs), later spreading with clinical use. By contrast, synthetic antibiotics began without pre-existing ARGs, yet bacteria soon adapted novel approaches to overcome them. In this perspective, we examine recent findings on ARG evolution, including their distribution in environmental bacteria, host range, and underlying molecular mechanisms of ARGs for bacterial adaptation against these antibiotics. To address these questions, we emphasize the urgent need for comprehensive studies to uncover the full range, distribution, and evolution of ARGs. Understanding these processes not only aids in developing effective strategies to combat ARGs but also provides critical insights into protein chemistry and advances protein engineering approaches.202540457171
9463180.9998Predictable and unpredictable evolution of antibiotic resistance. Evolution of bacteria towards antibiotic resistance is unavoidable as it represents a particular aspect of the general evolution of bacteria. Thus, at the very best, the only hope we can have in the field of resistance is to delay dissemination of resistant bacteria or resistance genes. Resistance to antibiotics in bacteria can result from mutations in resident structural or regulatory genes or from horizontal acquisition of foreign genetic information. In this review, we will consider the predictable future of the relationship between bacteria and antibiotics.200818397243
9215190.9998Bacterial type IV secretion systems and spread of antimicrobial resistance: a study of potential inhibitors to T4SS-based resistance spread. Antimicrobial resistance (AMR) is a major global health threat, mainly driven by the rapid spread of resistance genes through horizontal gene transfer (HGT). The Type IV Secretion System (T4SS) acts as a crucial molecular machinery that facilitates this process, allowing bacteria to transfer DNA, effector proteins, and virulence factors. This review systematically explores the structural and functional diversity of T4SS, its role in spreading AMR, and current methods for its inhibition. T4SS consists of a multi-protein complex that spans bacterial membranes, mediating conjugative plasmid transfer, host-pathogen interactions, and bacterial competition. Key components include ATPases, pilus structures, and membrane-associated proteins that show both conserved features and species-specific adaptations. These traits enable functional specialization across Gram-positive and Gram-negative bacteria, significantly contributing to the spread of vital resistance genes like extended-spectrum β-lactamases and carbapenemases via mobile genetic elements. Several approaches have been developed to inhibit T4SS and combat AMR. Small molecules targeting ATPase activity or protein interactions are promising, as are natural phytochemicals that interfere with conjugation. Bacteriophage therapy provides another strategy by specifically targeting plasmid-carrying bacteria. Host immune responses, such as innate immune recognition and secretory immunoglobulins, also show potential to influence T4SS activity. Although progress has been made, challenges remain, especially in developing selective inhibition methods that do not harm beneficial microbiota or host cells. Future research should focus on high-resolution structural studies to support rational drug design and preclinical testing of combination therapies that include T4SS inhibitors with existing antibiotics. Gaining a deeper understanding of T4SS regulation and host-pathogen interactions will be vital for creating targeted AMR strategies that also maintain ecological balance.202540956426