Antibiotics, Resistome and Resistance Mechanisms: A Bacterial Perspective. - Related Documents




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924401.0000Antibiotics, Resistome and Resistance Mechanisms: A Bacterial Perspective. History of mankind is regarded as struggle against infectious diseases. Rather than observing the withering away of bacterial diseases, antibiotic resistance has emerged as a serious global health concern. Medium of antibiotic resistance in bacteria varies greatly and comprises of target protection, target substitution, antibiotic detoxification and block of intracellular antibiotic accumulation. Further aggravation to prevailing situation arose on observing bacteria gradually becoming resistant to different classes of antibiotics through acquisition of resistance genes from same and different genera of bacteria. Attributing bacteria with feature of better adaptability, dispersal of antibiotic resistance genes to minimize effects of antibiotics by various means including horizontal gene transfer (conjugation, transformation, and transduction), Mobile genetic elements (plasmids, transposons, insertion sequences, integrons, and integrative-conjugative elements) and bacterial toxin-antitoxin system led to speedy bloom of antibiotic resistance amongst bacteria. Proficiency of bacteria to obtain resistance genes generated an unpleasant situation; a grave, but a lot unacknowledged, feature of resistance gene transfer.201830298054
924610.9998Horizontal Gene Transfer Systems for Spread of Antibiotic Resistance in Gram-Negative Bacteria. Antibiotic-resistant bacteria have become a significant global threat to public health due to the increasing difficulty in treatment. These bacteria acquire resistance by incorporating various antibiotic resistance genes (ARGs) through specialized gene transfer mechanisms, allowing them to evade antibiotic attacks. Conjugation, transformation, and transduction are well-established mechanisms that drive the acquisition and dissemination of ARGs in Gram-negative bacteria. In particular, the horizontal transfer of plasmids carrying multiple ARGs is highly problematic, as it can instantly convert susceptible bacteria into multidrug-resistant ones. Transduction, mediated by bacteriophages that package ARG-containing chromosomal DNA from host cells, also plays a crucial role in ARG spread without requiring direct cell-to-cell contact. Recently, a novel horizontal gene transfer (HGT) mechanism involving outer membrane vesicles (OMVs) has been identified as a key player in ARG dissemination. OMVs-nanoscale, spherical structures produced by bacteria during growth-have been found to carry small plasmids and chromosomal DNA fragments containing ARGs from their host bacteria. This newly discovered transfer process, termed "vesiduction," enables intercellular DNA exchange and further contributes to the spread of antibiotic resistance. Additionally, mobile genetic elements such as transposons, insertion sequences, and site-specific recombination systems like integrons facilitate rearrangement of ARGs, including their translocation between chromosomes and plasmids. This review explores the molecular mechanisms underlying the HGT of ARGs, with a particular focus on clinically isolated antibiotic-resistant Gram-negative bacteria.202540370256
924520.9998Type 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.202032903459
401130.9998Horizontal Gene Transfer of Antibiotic Resistance Genes in Biofilms. Most bacteria attach to biotic or abiotic surfaces and are embedded in a complex matrix which is known as biofilm. Biofilm formation is especially worrisome in clinical settings as it hinders the treatment of infections with antibiotics due to the facilitated acquisition of antibiotic resistance genes (ARGs). Environmental settings are now considered as pivotal for driving biofilm formation, biofilm-mediated antibiotic resistance development and dissemination. Several studies have demonstrated that environmental biofilms can be hotspots for the dissemination of ARGs. These genes can be encoded on mobile genetic elements (MGEs) such as conjugative and mobilizable plasmids or integrative and conjugative elements (ICEs). ARGs can be rapidly transferred through horizontal gene transfer (HGT) which has been shown to occur more frequently in biofilms than in planktonic cultures. Biofilm models are promising tools to mimic natural biofilms to study the dissemination of ARGs via HGT. This review summarizes the state-of-the-art of biofilm studies and the techniques that visualize the three main HGT mechanisms in biofilms: transformation, transduction, and conjugation.202336830238
401240.9998Augmented dissemination of antibiotic resistance elicited by non-antibiotic factors. The emergence and rapid spread of antibiotic resistance seriously compromise the clinical efficacy of current antibiotic therapies, representing a serious public health threat worldwide. Generally, drug-susceptible bacteria can acquire antibiotic resistance through genetic mutation or gene transfer, among which horizontal gene transfer (HGT) plays a dominant role. It is widely acknowledged that the sub-inhibitory concentrations of antibiotics are the key drivers in promoting the transmission of antibiotic resistance. However, accumulating evidence in recent years has shown that in addition to antibiotics, non-antibiotics can also accelerate the horizontal transfer of antibiotic resistance genes (ARGs). Nevertheless, the roles and potential mechanisms of non-antibiotic factors in the transmission of ARGs remain largely underestimated. In this review, we depict the four pathways of HGT and their differences, including conjugation, transformation, transduction and vesiduction. We summarize non-antibiotic factors accounting for the enhanced horizontal transfer of ARGs and their underlying molecular mechanisms. Finally, we discuss the limitations and implications of current studies.202337327521
401350.9998Correlation between Exogenous Compounds and the Horizontal Transfer of Plasmid-Borne Antibiotic Resistance Genes. The global spread of antibiotic resistance has posed a serious threat to public healthcare and undermined decades of progress made in the fight against bacterial infections. It has been demonstrated that the lack of novel effective antibiotics and rapid spread of antibiotic resistance genes via horizontal transfer in the ecosystem are mainly responsible for this crisis. Notably, plasmid-mediated horizontal transfer of antibiotic resistance genes (ARGs) is recognized as the most dominant dissemination pathway of ARGs in humans, animals and environmental settings. Antibiotic selective pressure has always been regarded as one of the crucial contributors to promoting the dissemination of antibiotic resistance through horizontal gene transfer (HGT). However, the roles of exogenous compounds and particularly non-antibiotic drugs in the spread of ARGs are still underappreciated. In this review, we first summarize the major pathways of HGT in bacteria, including conjugation, transformation, transduction and vesiduction. Subsequently, an overview of these compounds capable of promoting the HGT is presented, which guides to the formulation of more reasonable dosing regimens and drug residue standards in clinical practice. By contrast, these compounds that display an inhibition effect on HGT are also highlighted, which provides a unique strategy to minimize the spread of ARGs. Lastly, we discuss the implementations and challenges in bringing these HGT inhibitors into clinical trials.202032784449
403960.9998Acquired antibiotic resistance genes: an overview. In this review an overview is given on antibiotic resistance (AR) mechanisms with special attentions to the AR genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance, attention is also paid to mobile genetic elements such as plasmids, transposons, and integrons, which are associated with AR genes, and involved in the dispersal of antimicrobial determinants between different bacteria.201122046172
949370.9998Regulatory 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
983880.9998Interactions between plasmids and other mobile genetic elements affect their transmission and persistence. Plasmids are genetic elements that play a role in bacterial evolution by providing new genes that promote adaptation to diverse conditions. Plasmids are also known to reduce bacterial competitiveness in the absence of selection for plasmid-encoded traits. It is easier to understand plasmid persistence when considering the evidence that plasmid maintenance can improve during co-evolution with the bacterial host, i.e. the chromosome. However, bacteria isolated from nature often harbor diverse mobile elements: phages, transposons, genomic islands and even other plasmids. Recent interest has emerged on the role such elements play on the persistence and evolution of plasmids. Here, we mainly review interactions between different plasmids, but also discuss their interactions with other genetic elements. We focus on interactions that impact fundamental plasmid traits, such as the fitness effect imposed on their hosts and the transfer efficiency into new host cells. We illustrate these phenomena with examples concerning clinically relevant organisms and the spread of plasmids carrying antibiotic resistance genes and virulence factors.201930771401
401690.9998Antimicrobial-induced horizontal transfer of antimicrobial resistance genes in bacteria: a mini-review. The emergence and spread of antimicrobial resistance (AMR) among pathogenic bacteria constitute an accelerating crisis for public health. The selective pressures caused by increased use and misuse of antimicrobials in medicine and livestock production have accelerated the overall selection of resistant bacteria. In addition, horizontal gene transfer (HGT) plays an important role in the spread of resistance genes, for example mobilizing reservoirs of AMR from commensal bacteria into pathogenic ones. Antimicrobials, besides antibacterial function, also result in undesirable effects in the microbial populations, including the stimulation of HGT. The main aim of this narrative review was to present an overview of the current knowledge of the impact of antimicrobials on HGT in bacteria, including the effects of transformation, transduction and conjugation, as well as other less well-studied mechanisms of HGT. It is widely accepted that conjugation plays a major role in the spread of AMR in bacteria, and the focus of this review is therefore mainly on the evidence provided that antimicrobial treatment affects this process. Other mechanisms of HGT have so far been deemed less important in this respect; however, recent discoveries suggest their role may be larger than previously thought, and the review provides an update on the rather limited knowledge currently available regarding the impact of antimicrobial treatment on these processes as well. A conclusion from the review is that there is an urgent need to investigate the mechanisms of antimicrobial-induced HGT, since this will be critical for developing new strategies to combat the spread of AMR.202234894259
4014100.9998Dissemination of Antimicrobial Resistance in Microbial Ecosystems through Horizontal Gene Transfer. The emergence and spread of antibiotic resistance among pathogenic bacteria has been a rising problem for public health in recent decades. It is becoming increasingly recognized that not only antibiotic resistance genes (ARGs) encountered in clinical pathogens are of relevance, but rather, all pathogenic, commensal as well as environmental bacteria-and also mobile genetic elements and bacteriophages-form a reservoir of ARGs (the resistome) from which pathogenic bacteria can acquire resistance via horizontal gene transfer (HGT). HGT has caused antibiotic resistance to spread from commensal and environmental species to pathogenic ones, as has been shown for some clinically important ARGs. Of the three canonical mechanisms of HGT, conjugation is thought to have the greatest influence on the dissemination of ARGs. While transformation and transduction are deemed less important, recent discoveries suggest their role may be larger than previously thought. Understanding the extent of the resistome and how its mobilization to pathogenic bacteria takes place is essential for efforts to control the dissemination of these genes. Here, we will discuss the concept of the resistome, provide examples of HGT of clinically relevant ARGs and present an overview of the current knowledge of the contributions the various HGT mechanisms make to the spread of antibiotic resistance.201626925045
4009110.9998Unraveling the role of mobile genetic elements in antibiotic resistance transmission and defense strategies in bacteria. Irrational antibiotic use contributes to the development of antibiotic resistance in bacteria, which is a major cause of healthcare-associated infections globally. Molecular research has shown that multiple resistance frequently develops from the uptake of pre-existing resistance genes, which are subsequently intensified under selective pressures. Resistant genes spread and are acquired through mobile genetic elements which are essential for facilitating horizontal gene transfer. MGEs have been identified as carriers of genetic material and are a significant player in evolutionary processes. These include insertion sequences, transposons, integrative and conjugative elements, plasmids, and genomic islands, all of which can transfer between and within DNA molecules. With an emphasis on pathogenic bacteria, this review highlights the salient features of the MGEs that contribute to the development and spread of antibiotic resistance. MGEs carry non-essential genes, including AMR and virulence genes, which can enhance the adaptability and fitness of their bacterial hosts. These elements employ evolutionary strategies to facilitate their replication and dissemination, thus enabling survival without positive selection for the harboring of beneficial genes.202540810119
9494120.9998Within-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
4045130.9997Bacterial resistance to antimicrobial agents and its impact on veterinary and human medicine. BACKGROUND: Antimicrobial resistance has become a major challenge in veterinary medicine, particularly in the context of bacterial pathogens that play a role in both humans and animals. OBJECTIVES: This review serves as an update on acquired resistance mechanisms in bacterial pathogens of human and animal origin, including examples of transfer of resistant pathogens between hosts and of resistance genes between bacteria. RESULTS: Acquired resistance is based on resistance-mediating mutations or on mobile resistance genes. Although mutations are transferred vertically, mobile resistance genes are also transferred horizontally (by transformation, transduction or conjugation/mobilization), contributing to the dissemination of resistance. Mobile genes specifying any of the three major resistance mechanisms - enzymatic inactivation, reduced intracellular accumulation or modification of the cellular target sites - have been found in a variety of bacteria that may be isolated from animals. Such resistance genes are associated with plasmids, transposons, gene cassettes, integrative and conjugative elements or other mobile elements. Bacteria, including zoonotic pathogens, can be exchanged between animals and humans mainly via direct contact, but also via dust, aerosols or foods. Proof of the direction of transfer of resistant bacteria can be difficult and depends on the location of resistance genes or mutations in the chromosomal DNA or on a mobile element. CONCLUSION: The wide variety in resistance and resistance transfer mechanisms will continue to ensure the success of bacterial pathogens in the future. Our strategies to counteract resistance and preserve the efficacy of antimicrobial agents need to be equally diverse and resourceful.201727581211
4006140.9997Targeting Plasmids to Limit Acquisition and Transmission of Antimicrobial Resistance. Antimicrobial resistance (AMR) is a significant global threat to both public health and the environment. The emergence and expansion of AMR is sustained by the enormous diversity and mobility of antimicrobial resistance genes (ARGs). Different mechanisms of horizontal gene transfer (HGT), including conjugation, transduction, and transformation, have facilitated the accumulation and dissemination of ARGs in Gram-negative and Gram-positive bacteria. This has resulted in the development of multidrug resistance in some bacteria. The most clinically significant ARGs are usually located on different mobile genetic elements (MGEs) that can move intracellularly (between the bacterial chromosome and plasmids) or intercellularly (within the same species or between different species or genera). Resistance plasmids play a central role both in HGT and as support elements for other MGEs, in which ARGs are assembled by transposition and recombination mechanisms. Considering the crucial role of MGEs in the acquisition and transmission of ARGs, a potential strategy to control AMR is to eliminate MGEs. This review discusses current progress on the development of chemical and biological approaches for the elimination of ARG carriers.202032435238
9711150.9997Horizontal DNA transfer between bacteria in the environment. In the environment horizontal DNA transfer between various bacterial species and genera takes place by transformation, transduction, but mainly by conjugation. Conjugation is responsible for the spread of genes coding for antibiotic resistance and xenobiotic degradation. Transfer events are reported in animal, rhizosphere and phylloplane ecosystems and in non polluted and polluted water and soil. Genetic exchange between Bacteria and Archaea is also observed. Evaluation of the extent of interspecies gene transfer is crucial in view of the deliberate release of a variety of unmodified and genetically modified microorganisms into the natural environments.200314743976
9696160.9997Evolution 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.19938212510
9481170.9997Genetic 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
9295180.9997Biological activities specified by antibiotic resistance plasmids. Bacteria can display resistance to a wide spectrum of noxious agents and environmental conditions, and these properties are often mediated by genes located on extrachromosomal DNA elements called plasmids. Replication, vertical and horizontal transmission and evolution of these elements are discussed, and examples of the genes responsible for the resistance phenotypes are given. Selective forces that drive the evolution of new combinations of bacterial properties of particular importance in clinical situations are analysed.19863542928
9285190.9997Bacterial genetic exchange in nature. Most bacteria are haploid organisms containing only one copy of each gene per cell for most of the growth cycle. This means that the chance for correcting random mutations in bacterial genes would depend entirely on the complementarity inherent in DNA structures, unless homologous DNA sequences can be imported from outside the cell. Bacteria, like all living organisms have evolved at least one autonomous mechanism, conjugation, for exchanging portions of genetic materials between two related cells. The ecological benefits of conjugation include the expansion of metabolic versatility and resistance to hazardous environmental conditions. Natural bacterial genetic exchange also occurs through virus infections (transduction) and through the uptake of extracellular DNA (transformation). The origin and ecological benefits of transduction and transformation are difficult to assess because they are driven by factors external to the affected cell. Bacterial genetic exchange has implications for the evolution of phenotypes that are either beneficial to humans, such as biodegradation of toxic xenobiotic chemicals, or that are detrimental, such as the evolution of pathogenesis and the spread of antibiotic resistance. Understanding natural bacterial genetic exchange mechanisms is also relevant to the assessment of dispersal risks associated with genetically engineered bacteria and recombinant genes in the environment.19958533067