Ecological and evolutionary mechanisms driving within-patient emergence of antimicrobial resistance. - Related Documents




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948301.0000Ecological 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
948510.9999Evolution 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
967420.9999Global epistasis in plasmid-mediated antimicrobial resistance. Antimicrobial resistance (AMR) in bacteria is a major public health threat and conjugative plasmids play a key role in the dissemination of AMR genes among bacterial pathogens. Interestingly, the association between AMR plasmids and pathogens is not random and certain associations spread successfully at a global scale. The burst of genome sequencing has increased the resolution of epidemiological programs, broadening our understanding of plasmid distribution in bacterial populations. Despite the immense value of these studies, our ability to predict future plasmid-bacteria associations remains limited. Numerous empirical studies have recently reported systematic patterns in genetic interactions that enable predictability, in a phenomenon known as global epistasis. In this perspective, we argue that global epistasis patterns hold the potential to predict interactions between plasmids and bacterial genomes, thereby facilitating the prediction of future successful associations. To assess the validity of this idea, we use previously published data to identify global epistasis patterns in clinically relevant plasmid-bacteria associations. Furthermore, using simple mechanistic models of antibiotic resistance, we illustrate how global epistasis patterns may allow us to generate new hypotheses on the mechanisms associated with successful plasmid-bacteria associations. Collectively, we aim at illustrating the relevance of exploring global epistasis in the context of plasmid biology.202438409539
408530.9999The antibiotic resistome. IMPORTANCE OF THE FIELD: Antibiotics are essential for the treatment of bacterial infections and are among our most important drugs. Resistance has emerged to all classes of antibiotics in clinical use. Antibiotic resistance has, proven inevitable and very often it emerges rapidly after the introduction of a drug into the clinic. There is, therefore, a great interest in understanding the origins, scope and evolution of antibiotic resistance. AREAS COVERED IN THIS REVIEW: The review discusses the concept of the antibiotic resistome, which is the collection of all genes that directly or indirectly contribute to antibiotic resistance. WHAT THE READER WILL GAIN: The review seeks to assemble current knowledge of the resistome concept as a means of understanding the totality of resistance and not just resistance in pathogenic bacteria. TAKE HOME MESSAGE: The concept of the antibiotic resistome provides a framework for the study and understanding of how resistance emerges and evolves. Furthermore, the study of the resistome reveals strategies that can be applied in new antibiotic discoveries.201022827799
948740.9999Molecular mechanisms of antibiotic resistance revisited. Antibiotic resistance is a global health emergency, with resistance detected to all antibiotics currently in clinical use and only a few novel drugs in the pipeline. Understanding the molecular mechanisms that bacteria use to resist the action of antimicrobials is critical to recognize global patterns of resistance and to improve the use of current drugs, as well as for the design of new drugs less susceptible to resistance development and novel strategies to combat resistance. In this Review, we explore recent advances in understanding how resistance genes contribute to the biology of the host, new structural details of relevant molecular events underpinning resistance, the identification of new resistance gene families and the interactions between different resistance mechanisms. Finally, we discuss how we can use this information to develop the next generation of antimicrobial therapies.202336411397
408950.9999Genetic mechanisms of antibiotic resistance and virulence in Acinetobacter baumannii: background, challenges and future prospects. With the advent of the multidrug-resistant era, many opportunistic pathogens including the species Acinetobacter baumannii have gained prominence and pose a major global threat to clinical health care. Pathogenicity in bacteria is genetically regulated by a complex network of transcription and virulence factors and a brief overview of the major investigations on comprehending these processes over the past few decades in A. baumanni are compiled here. Many investigators have employed genome sequencing techniques to identify the regions that contribute to antibiotic resistance and comparative genomics to study sequence similarities to understand evolutionary trends of resistance gene transfers between isolates. A summary of these studies given here provides an insight into the invasion and successful colonization of the species. The individual roles played by different genes, regulators & promoters, enzymes, metal ions as well as mobile elements in influencing antibiotic resistance are briefly discussed. Precautionary measures and prospects for developing future strategies by exploring promising new research targets in effective control of multidrug resistant A. baumannii are also analyzed.202032303957
948660.9999Acquired 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
948870.9999Minimizing potential resistance: the molecular view. The major contribution of molecular biology to the study of antibiotic resistance has been the elucidation of nearly all biochemical mechanisms of resistance and the routes for dissemination of genetic information among bacteria. In this review, we consider the potential contribution of molecular biology to counteracting the evolution of resistant bacteria. In particular, we emphasize the fact that fundamental approaches have had direct practical effects on minimizing potential resistance: by improving interpretation of resistance phenotypes, by providing more adequate human therapy, by fostering more prudent use of antibiotics, and by allowing the rational design of new drugs that evade existing resistance mechanisms or address unexploited targets.200111524711
955880.9999Antimicrobial Resistance: Enzymes, Proteins, and Computational Resources. Antimicrobial resistance (AMR) is an important health concern rooted in antibiotic misuse and overuse, resulting in drug-resistant bacteria. However, resistance to these antimicrobials developed as soon as they were administered. Several variables lead to the progression of antimicrobial resistance (AMR), making it a multifaceted challenge for healthcare systems worldwide, such as erroneous diagnosis, inappropriate prescription, incomplete treatment, and many more. Getting an in-depth idea about the mechanism underlying AMR development is essential to overcome this. This review aims to provide information on how various enzymes or proteins aid in the antimicrobial resistance mechanisms and also highlight the clinical perspective of AMR, emphasizing its growing impact on patient outcomes, and incorporate the latest recent data from the World Health Organisation (WHO), underscoring the global urgency of the AMR crisis, with specific attention to trends observed in recent years. Additionally, it is intended to provide ideas about inhibitors that can inhibit the mechanism of antibiotic resistance and also to provide an idea about numerous computational resources available that can be employed to predict genes and/or proteins and enzymes involved in various antibiotic resistance mechanisms.202540770471
948290.9999Gene flow, mobile genetic elements and the recruitment of antibiotic resistance genes into Gram-negative pathogens. Antibiotics were one of the great discoveries of the 20th century. However, resistance appeared even in the earliest years of the antibiotic era. Antibiotic resistance continues to become worse, despite the ever-increasing resources devoted to combat the problem. One of the most important factors in the development of resistance to antibiotics is the remarkable ability of bacteria to share genetic resources via Lateral Gene Transfer (LGT). LGT occurs on a global scale, such that in theory, any gene in any organism anywhere in the microbial biosphere might be mobilized and spread. With sufficiently strong selection, any gene may spread to a point where it establishes a global presence. From an antibiotic resistance perspective, this means that a resistance phenotype can appear in a diverse range of infections around the globe nearly simultaneously. We discuss the forces and agents that make this LGT possible and argue that the problem of resistance can ultimately only be managed by understanding the problem from a broad ecological and evolutionary perspective. We also argue that human activities are exacerbating the problem by increasing the tempo of LGT and bacterial evolution for many traits that are important to humans.201121517914
9494100.9999Within-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
9683110.9999Antimicrobial 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
9701120.9999Environmental factors influencing the development and spread of antibiotic resistance. Antibiotic resistance and its wider implications present us with a growing healthcare crisis. Recent research points to the environment as an important component for the transmission of resistant bacteria and in the emergence of resistant pathogens. However, a deeper understanding of the evolutionary and ecological processes that lead to clinical appearance of resistance genes is still lacking, as is knowledge of environmental dispersal barriers. This calls for better models of how resistance genes evolve, are mobilized, transferred and disseminated in the environment. Here, we attempt to define the ecological and evolutionary environmental factors that contribute to resistance development and transmission. Although mobilization of resistance genes likely occurs continuously, the great majority of such genetic events do not lead to the establishment of novel resistance factors in bacterial populations, unless there is a selection pressure for maintaining them or their fitness costs are negligible. To enable preventative measures it is therefore critical to investigate under what conditions and to what extent environmental selection for resistance takes place. In addition, understanding dispersal barriers is not only key to evaluate risks, but also to prevent resistant pathogens, as well as novel resistance genes, from reaching humans.201829069382
9484130.9999Phage-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
9534140.9998Defining 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
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
4072160.9998A horizontal transmission of genetic information and its importance for development of antibiotics resistance. Genetic information is transmitted among organisms through two pathways - vertically from generation to generation (from parents to progeny) and horizontally (laterally) by direct exchange of genetic material across species barriers. These are primarily prokaryotes, in which the exchange of genes or whole gene segments by horizontal transmission is quite common. They can dynamically and in a relatively short time generate highly diverse genomes, which does not allow the vertical transmission. As a result, prokaryotes can rapidly acquire new properties such as virulence and pathogenicity as well as resistance to toxins, including antibiotics, by which they increase their adaptability. Therefore, reinfection-resistant microorganisms are always more difficult to treat than infections caused by non-resistant bacteria. Antibiotic resistance today is a global problem of health care service. Not only does the number of diseases caused by resistant pathogenic strains of bacteria increase, but also the cost of treatment increases disproportionately, the length of hospitalization is prolonged, and mortality is often rising. Therefore, when indicating antibiotic therapy, it is important to keep in mind that both overuse and abuse of antibiotics contribute to the spread of antibiotic resistance genes. This is equally true for antibiotic applications in veterinary medicine, agriculture, including aquacultures, or in the food industry. Keywords: horizontal transmission of genetic information, endosymbiosis, antibiotic resistance, risks of the emergence and spread of antibiotic resistance, prevention of antibiotic resistance.201830441943
9533170.9998The 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
4086180.9998Insights into antibiotic resistance through metagenomic approaches. The consequences of bacterial infections have been curtailed by the introduction of a wide range of antibiotics. However, infections continue to be a leading cause of mortality, in part due to the evolution and acquisition of antibiotic-resistance genes. Antibiotic misuse and overprescription have created a driving force influencing the selection of resistance. Despite the problem of antibiotic resistance in infectious bacteria, little is known about the diversity, distribution and origins of resistance genes, especially for the unculturable majority of environmental bacteria. Functional and sequence-based metagenomics have been used for the discovery of novel resistance determinants and the improved understanding of antibiotic-resistance mechanisms in clinical and natural environments. This review discusses recent findings and future challenges in the study of antibiotic resistance through metagenomic approaches.201222191448
4022190.9998Antibiotic resistance in the environment. Antibiotic resistance is a global health challenge, involving the transfer of bacteria and genes between humans, animals and the environment. Although multiple barriers restrict the flow of both bacteria and genes, pathogens recurrently acquire new resistance factors from other species, thereby reducing our ability to prevent and treat bacterial infections. Evolutionary events that lead to the emergence of new resistance factors in pathogens are rare and challenging to predict, but may be associated with vast ramifications. Transmission events of already widespread resistant strains are, on the other hand, common, quantifiable and more predictable, but the consequences of each event are limited. Quantifying the pathways and identifying the drivers of and bottlenecks for environmental evolution and transmission of antibiotic resistance are key components to understand and manage the resistance crisis as a whole. In this Review, we present our current understanding of the roles of the environment, including antibiotic pollution, in resistance evolution, in transmission and as a mere reflection of the regional antibiotic resistance situation in the clinic. We provide a perspective on current evidence, describe risk scenarios, discuss methods for surveillance and the assessment of potential drivers, and finally identify some actions to mitigate risks.202234737424