Type IV Coupling Proteins as Potential Targets to Control the Dissemination of Antibiotic Resistance. - Related Documents




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924501.0000Type 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
930910.9999Plasmid encoded antibiotic resistance: acquisition and transfer of antibiotic resistance genes in bacteria. Bacteria have existed on Earth for three billion years or so and have become adept at protecting themselves against toxic chemicals. Antibiotics have been in clinical use for a little more than 6 decades. That antibiotic resistance is now a major clinical problem all over the world attests to the success and speed of bacterial adaptation. Mechanisms of antibiotic resistance in bacteria are varied and include target protection, target substitution, antibiotic detoxification and block of intracellular antibiotic accumulation. Acquisition of genes needed to elaborate the various mechanisms is greatly aided by a variety of promiscuous gene transfer systems, such as bacterial conjugative plasmids, transposable elements and integron systems, that move genes from one DNA system to another and from one bacterial cell to another, not necessarily one related to the gene donor. Bacterial plasmids serve as the scaffold on which are assembled arrays of antibiotic resistance genes, by transposition (transposable elements and ISCR mediated transposition) and site-specific recombination mechanisms (integron gene cassettes).The evidence suggests that antibiotic resistance genes in human bacterial pathogens originate from a multitude of bacterial sources, indicating that the genomes of all bacteria can be considered as a single global gene pool into which most, if not all, bacteria can dip for genes necessary for survival. In terms of antibiotic resistance, plasmids serve a central role, as the vehicles for resistance gene capture and their subsequent dissemination. These various aspects of bacterial resistance to antibiotics will be explored in this presentation.200818193080
967720.9999Inhibiting conjugation as a tool in the fight against antibiotic resistance. Antibiotic resistance, especially in gram-negative bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid-encoded conjugation system and the host-encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addition to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics.201930343487
969630.9999Evolution 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
924640.9999Horizontal 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
404550.9999Bacterial 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
983860.9999Interactions 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
967870.9999Molecular basis of bacterial disinfectant resistance. Antibiotic resistance could accelerate humanity towards an already fast-approaching post-antibiotic era, where disinfectants and effective biosecurity measures will be critically important to control microbial diseases. Disinfectant resistance has the potential to change our way of life from compromising food security to threatening our medical health systems. Resistance to antimicrobial agents occurs through either intrinsic or acquired resistance mechanisms. Acquired resistance occurs through the efficient transfer of mobile genetic elements, which can carry single, or multiple resistance determinants. Drug resistance genes may form part of integrons, transposons and insertions sequences which are capable of intracellular transfer onto plasmids or gene cassettes. Thereafter, resistance plasmids and gene cassettes mobilize by self-transmission between bacteria, increasing the prevalence of drug resistance determinants in a bacterial population. An accumulation of drug resistance genes through these mechanisms gives rise to multidrug resistant (MDR) bacteria. The study of this mobility is integral to safeguard current antibiotics, disinfectants and other antimicrobials. Literature evidence, however, indicates that knowledge regarding disinfectant resistance is severly limited. Genome engineering such as the CRISPR-Cas system, has identified disinfectant resistance genes, and reversed resistance altogether in certain prokaryotes. Demonstrating that these techniques could prove invaluable in the combat against disinfectant resistance by uncovering the secrets of MDR bacteria.202031830738
968880.9999Indirect Selection against Antibiotic Resistance via Specialized Plasmid-Dependent Bacteriophages. Antibiotic resistance genes of important Gram-negative bacterial pathogens are residing in mobile genetic elements such as conjugative plasmids. These elements rapidly disperse between cells when antibiotics are present and hence our continuous use of antimicrobials selects for elements that often harbor multiple resistance genes. Plasmid-dependent (or male-specific or, in some cases, pilus-dependent) bacteriophages are bacterial viruses that infect specifically bacteria that carry certain plasmids. The introduction of these specialized phages into a plasmid-abundant bacterial community has many beneficial effects from an anthropocentric viewpoint: the majority of the plasmids are lost while the remaining plasmids acquire mutations that make them untransferable between pathogens. Recently, bacteriophage-based therapies have become a more acceptable choice to treat multi-resistant bacterial infections. Accordingly, there is a possibility to utilize these specialized phages, which are not dependent on any particular pathogenic species or strain but rather on the resistance-providing elements, in order to improve or enlengthen the lifespan of conventional antibiotic approaches. Here, we take a snapshot of the current knowledge of plasmid-dependent bacteriophages.202133572937
423990.9999Bacterial resistance. Pathogenic bacteria remain adaptable to an increasingly hostile environment and a wider variety of more potent antibiotics. Organisms not intrinsically prepared for defense have been able to acquire resistance to newer antimicrobial agents. Chromosomal mutations alone cannot account for the rapid emergence and spread of antibiotic resistance. It has been established that plasmids and transposons are particularly important in the evolution of antibiotic-resistant bacteria. Plasmid- or transposon-mediated resistance provides the bacteria with pre-evolved genes refined to express high-level resistance. In particular, transposons can transfer these resistance determinants in diverse bacterial species, and nature provides in humans and animals large intestinal reservoirs in which such communications are facilitated. Antibiotic therapy exerts selection pressures on bacteria. Eradication or marked reduction in the populations of susceptible organisms promotes the overgrowth of intrinsically resistant strains and favors those resistant as a result of favorable chromosomal mutations or via plasmids or transposons. In our hospitals, where antibiotic consumption continues to increase, the nosocomial flora consists of many resistant bacteria, and infections acquired in the nosocomial setting are now far more severe than their community-acquired counterparts. There is convincing evidence that infection control measures must take into further consideration the contribution of the hospital worker as carrier and mediator of antibiotic resistance.19911649425
9305100.9999Control of genes for conjugative transfer of plasmids and other mobile elements. Conjugative transfer is a primary means of spread of mobile genetic elements (plasmids and transposons) between bacteria.It leads to the dissemination and evolution of the genes (such as those conferring resistance to antibiotics) which are carried by the plasmid. Expression of the plasmid genes needed for conjugative transfer is tightly regulated so as to minimise the burden on the host. For plasmids such as those belonging to the IncP group this results in downregulation of the transfer genes once all bacteria have a functional conjugative apparatus. For F-like plasmids (apart from F itself which is a derepressed mutant) tight control results in very few bacteria having a conjugative apparatus. Chance encounters between the rare transfer-proficient bacteria and a potential recipient initiate a cascade of transfer which can continue until all potential recipients have acquired the plasmid. Other systems express their transfer genes in response to specific stimuli. For the pheromone-responsive plasmids of Enterococcus it is small peptide signals from potential recipients which trigger the conjugative transfer genes. For the Ti plasmids of Agrobacterium it is the presence of wounded plants which are susceptible to infection which stimulates T-DNA transfer to plants. Transfer and integration of T-DNA induces production of opines which the plasmid-positive bacteria can utilise. They multiply and when they reach an appropriate density their plasmid transfer system is switched on to allow transfer of the Ti plasmid to other bacteria. Finally some conjugative transfer systems are induced by the antibiotics to which the elements confer resistance. Understanding these control circuits may help to modify management of microbial communities where plasmid transfer is either desirable or undesirable. z 1998 Published by Elsevier Science B.V.199825508777
9295110.9999Biological 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
3837120.9999Evolutionary Paths That Expand Plasmid Host-Range: Implications for Spread of Antibiotic Resistance. 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 naïve hosts, acquisition of this transposon also expanded the plasmid's host range, which has important implications for the spread of antibiotic resistance.201626668183
9493130.9999Regulatory 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
9679140.9999Integrons as the potential targets for combating multidrug resistance in Enterobacteriaceae using CRISPR- Cas9 technique. The emergence of multi-drug resistance (MDR) to pan-drug resistance (PDR) in Enterobacteriaceae has made treatment extremely challenging. Genetic mutations and horizontal gene transfer (HGT) through mobile genetic elements (MGEs) were frequently associated mechanisms of drug resistance in pathogens. However, transposons, plasmids, and integrons transfer MDR genes in bacterium via HGT much faster. Integrons are dsDNA segment that plays a crucial role in the adaptation and evolution of bacteria. They contain multiple gene cassettes that code for antibiotic resistance determinants that are expressed by a single promoter (Pc). Integrons are the cause of drug resistance in Enterobacteriaceae. Although alternatives to antibiotics such as bacteriophages, phage proteins, antimicrobial peptides, and natural compounds have been widely used to treat MDR infections, there have been limited efforts to reverse the antibiotic resistance ability of bacteria. Thus, silencing the genes harboured on MGEs achieved by Gene Editing Techniques (GETs) might prevent the spread of MDR. One such GETs, which has a simple design, good repeatability, low cost, and high efficiency, is CRISPR- Cas9 system. Thus, this review is a first of the kind that focuses on utilizing the structure of an integron to make it an ideal target for GETs like CRISPR- Cas9 systems.202337410611
4009150.9999Unraveling 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
9310160.9999Bacterial resistance to antibiotics. Effective antibacterial drugs have been available for nearly 50 years. After the introduction of each new such drug, whether chemically synthesized or a naturally occurring antibiotic, bacterial resistance to it has emerged. The genetic mechanisms by which bacteria have acquired resistance were quite unexpected; a new evolutionary pathways has been revealed. Although some antibiotic resistance has resulted from mutational changes in structural proteins--targets for the drugs' action--most has resulted from the acquisition of new, ready-made genes from an external source--that is, from another bacterium. Vectors of the resistance genes are plasmids--heritable DNA molecules that are transmissible between bacterial cells. Plasmids without antibiotic-resistance genes are common in all kinds of bacteria. Resistance plasmids have resulted from the insertion of new DNA sequences into previously existing plasmids. Thus, the spread of antibiotic resistance is at three levels: bacteria between people or animals; plasmids between bacteria; and transposable genes between plasmids.19846319093
4046170.9998Horizontal Gene Transfer and Its Association with Antibiotic Resistance in the Genus Aeromonas spp. The evolution of multidrug resistant bacteria to the most diverse antimicrobials known so far pose a serious problem to global public health. Currently, microorganisms that develop resistant phenotypes to multiple drugs are associated with high morbidity and mortality. This resistance is encoded by a group of genes termed 'bacterial resistome', divided in intrinsic and extrinsic resistome. The first one refers to the resistance displayed on an organism without previous exposure to an antibiotic not involving horizontal genetic transfer, and it can be acquired via mutations. The latter, on the contrary, is acquired exclusively via horizontal genetic transfer involving mobile genetic elements that constitute the 'bacterial mobilome'. This transfer is mediated by three different mechanisms: transduction, transformation, and conjugation. Recently, a problem of public health due to implications in the emergence of multi-drug resistance in Aeromonas spp. strains in water environments has been described. This is derived from the genetic material transfer via conjugation events. This is important, since bacteria that have acquired antibiotic resistance in natural environments can cause infections derived from their ingestion or direct contact with open wounds or mucosal tissue, which in turn, by their resistant nature, makes their eradication complex. Implications of the emergence of resistance in Aeromonas spp. by horizontal gene transfer on public health are discussed.201931540466
9397180.9998Conjugation Inhibitors Effectively Prevent Plasmid Transmission in Natural Environments. Plasmid conjugation is a major route for the spread of antibiotic resistance genes. Inhibiting conjugation has been proposed as a feasible strategy to stop or delay the propagation of antibiotic resistance genes. Several compounds have been shown to be conjugation inhibitors in vitro, specifically targeting the plasmid horizontal transfer machinery. However, the in vivo efficiency and the applicability of these compounds to clinical and environmental settings remained untested. Here we show that the synthetic fatty acid 2-hexadecynoic acid (2-HDA), when used as a fish food supplement, lowers the conjugation frequency of model plasmids up to 10-fold in controlled water microcosms. When added to the food for mice, 2-HDA diminished the conjugation efficiency 50-fold in controlled plasmid transfer assays carried out in the mouse gut. These results demonstrate the in vivo efficiency of conjugation inhibitors, paving the way for their potential application in clinical and environmental settings. IMPORTANCE The spread of antibiotic resistance is considered one of the major threats for global health in the immediate future. A key reason for the speed at which antibiotic resistance spread is the ability of bacteria to share genes with each other. Antibiotic resistance genes harbored in plasmids can be easily transferred to commensal and pathogenic bacteria through a process known as bacterial conjugation. Blocking conjugation is thus a potentially useful strategy to curtail the propagation of antibiotic resistance. Conjugation inhibitors (COINS) are a series of compounds that block conjugation in vitro. Here we show that COINS efficiently block plasmid transmission in two controlled natural environments, water microcosms and the mouse gut. These observations indicate that COIN therapy can be used to prevent the spread of antibiotic resistance.202134425705
4241190.9998Mechanisms of antimicrobial resistance and implications for epidemiology. The development of antibacterial agents has provided a means of treating bacterial diseases which were, previously, often fatal in both man and animal and thus represents one of the major advances of the 20th century. However, the efficacy of these agents is increasingly being compromised by the development of bacterial resistance to the drugs currently available for therapeutic use. Bacterial resistance can be combated in two ways. New drugs to which bacteria are susceptible can be developed and policies to contain the development and spread of resistance can be implemented. Both strategies require an understanding of the mechanisms of drug resistance, its epidemiology and the role of environmental factors in promoting resistance. Over the past thirty years our knowledge of bacterial resistance has increased dramatically mainly due to new technology that has become available. Bacteria are able to resist antibacterials by a variety of mechanisms: for example, altering the target to decrease susceptibility to the antibacterial, inactivating or destroying the drug, reducing drug transport into the cell or metabolic bypass. These drug resistance determinants are mediated via one of two distinct genetic mechanisms, a mutation in the bacterial chromosome or by a transmissible element; either a plasmid or a transposon. Significant differences exist between these two types of drug resistance as transmissible resistance, which is mainly plasmid-mediated, permits intraspecies and even interspecies transfer to occur. In contrast, chromosomal resistance can only be passed on to progeny. Transmissible antibacterial resistance is the major cause of concern as it can lead to the rapid spread of antibacterial resistance and has proven difficult, if not impossible, to eradicate. Furthermore, plasmids and transposons can code for multiple antibiotic resistance as well as virulence genes. Antibacterials for which transferable resistance has been identified include most commonly used antibacterials such as beta-lactams, aminoglycosides, macrolides, sulphonamides, tetracyclines, chloramphenicol and trimethoprim. One notable exception is the 4-quinolones for which plasmid-mediated resistance has yet to be identified.19938212509