Inactivation of antibiotics and the dissemination of resistance genes. - Related Documents




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442301.0000Inactivation of antibiotics and the dissemination of resistance genes. The emergence of multidrug-resistant bacteria is a phenomenon of concern to the clinician and the pharmaceutical industry, as it is the major cause of failure in the treatment of infectious diseases. The most common mechanism of resistance in pathogenic bacteria to antibiotics of the aminoglycoside, beta-lactam (penicillins and cephalosporins), and chloramphenicol types involves the enzymic inactivation of the antibiotic by hydrolysis or by formation of inactive derivatives. Such resistance determinants most probably were acquired by pathogenic bacteria from a pool of resistance genes in other microbial genera, including antibiotic-producing organisms. The resistance gene sequences were subsequently integrated by site-specific recombination into several classes of naturally occurring gene expression cassettes (typically "integrons") and disseminated within the microbial population by a variety of gene transfer mechanisms. Although bacterial conjugation once was believed to be restricted in host range, it now appears that this mechanism of transfer permits genetic exchange between many different bacterial genera in nature.19948153624
415210.9999Quinolone resistance: much more than predicted. Since quinolones are synthetic antibiotics, it was predicted that mutations in target genes would be the only mechanism through which resistance could be acquired, because there will not be quinolone-resistance genes in nature. Contrary to this prediction, a variety of elements ranging from efflux pumps, target-protecting proteins, and even quinolone-modifying enzymes have been shown to contribute to quinolone resistance. The finding of some of these elements in plasmids indicates that quinolone resistance can be transferable. As a result, there has been a developing interest on the reservoirs for quinolone-resistance genes and on the potential risks associated with the use of these antibiotics in non-clinical environments. As a matter of fact, plasmid-encoded, quinolone-resistance qnr genes originated in the chromosome of aquatic bacteria. Thus the use of quinolones in fish-farming might constitute a risk for the emergence of resistance. Failure to predict the development of quinolone resistance reinforces the need of taking into consideration the wide plasticity of biological systems for future predictions. This plasticity allows pathogens to deal with toxic compounds, including those with a synthetic origin as quinolones.201121687414
415120.9999Evolutionary relationships among genes for antibiotic resistance. The genes that determine resistance to antibiotics are commonly found encoded by extrachromosomal elements in bacteria. These were described first in Enterobacteriaceae and subsequently in a variety of other genera; their spread is associated with the increased use of antibiotics in human and animal medicine. Antibiotic-resistance genes that determine the production of enzymes which modify (detoxify) the antibiotics have been detected in antibiotic-producing organisms. It has been suggested that the producing strains provided the source of antibiotic-resistance genes that were then 'picked-up' by recombination. Recent studies of the nucleotide sequence of certain antibiotic-resistance genes indicate regions of strong homology in the encoded proteins. The implications of these similarities are discussed.19846559117
442430.9999Gene transfer, gentamicin resistance and enterococci. Enterococci are versatile pathogens by virtue of their ability to exhibit low-level intrinsic resistance to clinically useful antibiotics and their tolerance to adverse environmental conditions. In the last 20 years these pathogens have become progressively more difficult to treat because of their aptitude for acquiring antibiotic-resistance genes. Of increasing concern is the rapid dissemination of the AAC6'-APH2" bi-functional aminoglycoside modifying enzyme. This enzyme confers high-level resistance to gentamicin and all other related aminoglycosides with the exception of streptomycin. The gene conferring this phenotype has been associated with both narrow and broad host range plasmids, and has recently been found on conjugative transposons. The nature of these conjugative elements raises the possibility of the resistance gene spreading to other pathogenic bacteria.19979261754
414040.9999Use of antimicrobials in veterinary medicine and mechanisms of resistance. This review deals with the application of antimicrobial agents in veterinary medicine and food animal production and the possible consequences arising from the widespread and multipurpose use of antimicrobials. The various mechanisms that bacteria have developed to escape the inhibitory effects of the antimicrobials most frequently used in the veterinary field are reported in detail. Resistance of bacteria to tetracyclines, macrolide-lincosamide-streptogramin antibiotics, beta-lactam antibiotics, aminoglycosides, sulfonamides, trimethoprim, fluoroquinolones and chloramphenicol/florfenicol is described with regard to enzymatic inactivation, decreased intracellular drug accumulation and modification/protection/replacement of the target sites. In addition, basic information is given about mobile genetic elements which carry the respective resistance genes, such as plasmids, transposons, and gene cassettes/integrons, and their ways of spreading via conjugation, mobilisation, transduction, and transformation.200111432414
414950.9999Antibiotic resistance genes from the environment: a perspective through newly identified antibiotic resistance mechanisms in the clinical setting. Soil bacteria may contain antibiotic resistance genes responsible for different mechanisms that permit them to overcome the natural antibiotics present in the environment. This gene pool has been recently named the 'resistome', and its components can be mobilized into the microbial community affecting humans because of the participation of genetic platforms that efficiently facilitate the mobilization and maintenance of these resistance genes. Evidence for this transference has been suggested or demonstrated with newly identified widespread genes in multidrug-resistant bacteria. These resistance genes include those responsible for ribosomal methylases affecting aminoglycosides (armA, rtmB), methyltransferases affecting linezolid (cfr) or plasmid-mediated efflux pumps conferring low-level fluoroquinolone resistance (qepA), all of which are associated with antibiotic-producing bacteria. In addition, resistance genes whose ancestors have been identified in environmental isolates that are not recognized as antibiotic producers have also been recently detected. These include the qnr and the bla(CTX) genes compromising the activity of fluoroquinolones and extended-spectrum cephalosporins, respectively. The application of metagenomic tools and phylogenetic analysis will facilitate future identification of other new resistance genes and their corresponding ancestors in environmental bacteria, and will enable further exploration of the concept of the resistome as being a unique reservoir of antibiotic resistance genes and genetic elements participating in resistance gene transfer.200919220348
442560.9999Multidrug resistance in bacteria. Large amounts of antibiotics used for human therapy, as well as for farm animals and even for fish in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. Multidrug resistance in bacteria may be generated by one of two mechanisms. First, these bacteria may accumulate multiple genes, each coding for resistance to a single drug, within a single cell. This accumulation occurs typically on resistance (R) plasmids. Second, multidrug resistance may also occur by the increased expression of genes that code for multidrug efflux pumps, extruding a wide range of drugs. This review discusses our current knowledge on the molecular mechanisms involved in both types of resistance.200919231985
413370.9999Importance of integrons in the diffusion of resistance. Horizontal transfer of resistance genes is a successful mechanism for the transmission and dissemination of multiple drug resistance among bacterial pathogens. The impact of horizontally transmitted genetic determinants in the evolution of resistance is particularly evident when resistance genes are physically associated in clusters and transferred en bloc to the recipient cell. Recent advances in the molecular characterisation of antibiotic resistance mechanisms have highlighted the existence of genetic structures. called integrons, involved in the acquisition of resistance genes. These DNA elements have frequently been reported in multi-drug resistant strains isolated from animals and humans, and are located either on the bacterial chromosome or on broad-host-range plasmids. The role of integrons in the development of multiple resistance relies on their unique capacity to cluster and express drug resistance genes. Moreover, the spread of resistance genes among different replicons and their exchange between plasmid and bacterial chromosome are facilitated by the integration of integrons into transposable elements. The association of a highly efficient gene capture and expression system, together with the capacity for vertical and horizontal transmission of resistance genes represents a powerful weapon used by bacteria to combat the assault of antibiotics.200111432416
413480.9999Plasmid-Mediated Antimicrobial Resistance in Staphylococci and Other Firmicutes. In staphylococci and other Firmicutes, resistance to numerous classes of antimicrobial agents, which are commonly used in human and veterinary medicine, is mediated by genes that are associated with mobile genetic elements. The gene products of some of these antimicrobial resistance genes confer resistance to only specific members of a certain class of antimicrobial agents, whereas others confer resistance to the entire class or even to members of different classes of antimicrobial agents. The resistance mechanisms specified by the resistance genes fall into any of three major categories: active efflux, enzymatic inactivation, and modification/replacement/protection of the target sites of the antimicrobial agents. Among the mobile genetic elements that carry such resistance genes, plasmids play an important role as carriers of primarily plasmid-borne resistance genes, but also as vectors for nonconjugative and conjugative transposons that harbor resistance genes. Plasmids can be exchanged by horizontal gene transfer between members of the same species but also between bacteria belonging to different species and genera. Plasmids are highly flexible elements, and various mechanisms exist by which plasmids can recombine, form cointegrates, or become integrated in part or in toto into the chromosomal DNA or into other plasmids. As such, plasmids play a key role in the dissemination of antimicrobial resistance genes within the gene pool to which staphylococci and other Firmicutes have access. This chapter is intended to provide an overview of the current knowledge of plasmid-mediated antimicrobial resistance in staphylococci and other Firmicutes.201426104453
415390.9999Amino acid variation in the GyrA subunit of bacteria potentially associated with natural resistance to fluoroquinolone antibiotics. In studies of genetic diversity in natural microbial populations, we have analyzed nucleotide sequences in the quinolone resistance-determining region of the bacterial gyrA gene in ciprofloxacin-resistant and nonselected soil bacteria obtained from the environment. It is apparent that this sequence is highly variable, and resistance to fluoroquinolone antibiotics occurring in environmental populations of bacteria is due at least in part to natural sequence variation in this domain. We suggest that the development of new antimicrobial agents, including completely synthetic antimicrobials such as the fluoroquinolones, should incorporate the analysis of resistance mechanisms among microbes in natural environments; these studies could predict potential mechanisms of resistance to be encountered in subsequent clinical use of the agents and would guide chemical modification designed to evade resistance development.19979420056
4470100.9999R-factors in gram-positive and gram-negative aerobic bacteria selected by antimicrobial therapy. Populations of resistant bacteria emerge by the operation of selective pressure on resistant bacteria. The acquisition of resistance by sensitive bacteria is dependent upon the genetic determinant of the resistance, and its ability to move between different bacterial cells and within cells between different replicons. In contrast to chromosomal mediated resistance, plasmids and transposable elements coding for resistance to antibiotics have been the major factors in the spread of resistance and the prevalence of resistant bacteria in humans, farm animals and poultry. Different types of R-factors can be described. Resistance to ampicillin, tetracycline, chloramphenicol, gentamicin, trimethoprim, erythromycin may exemplify epidemiological aspects of resistance genes in Gram-negative and Gram-positive bacteria. The ecological destiny of resistant bacterial populations suggests the role of other factors than antibiotic resistance: characters of a particular host, host-plasmid relationship and properties which may lead to survival and adaptation in a given niche.19863547625
4240110.9999Genetics of antimicrobial resistance. Antimicrobial resistant strains of bacteria are an increasing threat to animal and human health. Resistance mechanisms to circumvent the toxic action of antimicrobials have been identified and described for all known antimicrobials currently available for clinical use in human and veterinary medicine. Acquired bacterial antibiotic resistance can result from the mutation of normal cellular genes, the acquisition of foreign resistance genes, or a combination of these two mechanisms. The most common resistance mechanisms employed by bacteria include enzymatic degradation or alteration of the antimicrobial, mutation in the antimicrobial target site, decreased cell wall permeability to antimicrobials, and active efflux of the antimicrobial across the cell membrane. The spread of mobile genetic elements such as plasmids, transposons, and integrons has greatly contributed to the rapid dissemination of antimicrobial resistance among several bacterial genera of human and veterinary importance. Antimicrobial resistance genes have been shown to accumulate on mobile elements, leading to a situation where multidrug resistance phenotypes can be transferred to a susceptible recipient via a single genetic event. The increasing prevalence of antimicrobial resistant bacterial pathogens has severe implications for the future treatment and prevention of infectious diseases in both animals and humans. The versatility with which bacteria adapt to their environment and exchange DNA between different genera highlights the need to implement effective antimicrobial stewardship and infection control programs in both human and veterinary medicine.200617127523
4043120.9999Mobile antibiotic resistance - the spread of genes determining the resistance of bacteria through food products. In recent years, more and more antibiotics have become ineffective in the treatment of bacterial nfections. The acquisition of antibiotic resistance by bacteria is associated with circulation of genes in the environment. Determinants of antibiotic resistance may be transferred to pathogenic bacteria. It has been shown that conjugation is one of the key mechanisms responsible for spread of antibiotic resistance genes, which is highly efficient and allows the barrier to restrictions and modifications to be avoided. Some conjugative modules enable the transfer of plasmids even between phylogenetically distant bacterial species. Many scientific reports indicate that food is one of the main reservoirs of these genes. Antibiotic resistance genes have been identified in meat products, milk, fruits and vegetables. The reason for such a wide spread of antibiotic resistance genes is the overuse of antibiotics by breeders of plants and animals, as well as by horizontal gene transfer. It was shown, that resistance determinants located on mobile genetic elements, which are isolated from food products, can easily be transferred to another niche. The antibiotic resistance genes have been in the environment for 30 000 years. Their removal from food products is not possible, but the risks associated with the emergence of multiresistant pathogenic strains are very large. The only option is to control the emergence, selection and spread of these genes. Therefore measures are sought to prevent horizontal transfer of genes. Promising concepts involve the combination of developmental biology, evolution and ecology in the fight against the spread of antibiotic resistance.201627383577
4241130.9999Mechanisms 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
9407140.9999Comparison of Antibiotic Resistance Mechanisms in Antibiotic-Producing and Pathogenic Bacteria. Antibiotic resistance poses a tremendous threat to human health. To overcome this problem, it is essential to know the mechanism of antibiotic resistance in antibiotic-producing and pathogenic bacteria. This paper deals with this problem from four points of view. First, the antibiotic resistance genes in producers are discussed related to their biosynthesis. Most resistance genes are present within the biosynthetic gene clusters, but some genes such as paromomycin acetyltransferases are located far outside the gene cluster. Second, when the antibiotic resistance genes in pathogens are compared with those in the producers, resistance mechanisms have dependency on antibiotic classes, and, in addition, new types of resistance mechanisms such as Eis aminoglycoside acetyltransferase and self-sacrifice proteins in enediyne antibiotics emerge in pathogens. Third, the relationships of the resistance genes between producers and pathogens are reevaluated at their amino acid sequence as well as nucleotide sequence levels. Pathogenic bacteria possess other resistance mechanisms than those in antibiotic producers. In addition, resistance mechanisms are little different between early stage of antibiotic use and the present time, e.g., β-lactam resistance in Staphylococcus aureus. Lastly, guanine + cytosine (GC) barrier in gene transfer to pathogenic bacteria is considered. Now, the resistance genes constitute resistome composed of complicated mixture from divergent environments.201931546630
4417150.9999Genetic mobility and distribution of tetracycline resistance determinants. Since 1953, tetracycline-resistant bacteria have been found increasingly in humans, animals, food and the environment. Tetracycline resistance is normally due to the acquisition of new genes and is primarily due to either energy-dependent efflux of tetracycline or protection of the ribosomes from its action. Gram-negative efflux genes are frequently associated with conjugative plasmids, whereas Gram-positive efflux genes are often found on small mobilizable plasmids or in the chromosome. The ribosomal protection genes are generally associated with conjugative transposons which have a preference for the chromosome. Recently, tetracycline resistance genes have been found in the genera Mycobacterium, Nocardia, Streptomyces and Treponema. The Tet M determinant codes for a ribosomal protection protein which can be found in Gram-positive, Gram-negative, cell-wall-free, aerobic, anaerobic, pathogenic, opportunistic and normal flora species. This promiscuous nature may be correlated with its location on a conjugative transposon and its ability to cross most biochemical and physical barriers found in bacteria. The Tet B efflux determinant is unlike other efflux gene products because it confers resistance to tetracycline, doxycycline and minocycline and has the widest host range of all Gram-negative efflux determinants. We have hypothesized that mobility and the environment of the bacteria may help influence the ultimate host range of specific tet genes. If we are to reverse the trend towards increasingly antibiotic-resistant pathogenic bacteria, we will need to change how antibiotics are used in both human and animal health as well as food production.19979189643
3833160.9999Fight evolution with evolution: plasmid-dependent phages with a wide host range prevent the spread of antibiotic resistance. The emergence of pathogenic bacteria resistant to multiple antibiotics is a serious worldwide public health concern. Whenever antibiotics are applied, the genes encoding for antibiotic resistance are selected for within bacterial populations. This has led to the prevalence of conjugative plasmids that carry resistance genes and can transfer themselves between diverse bacterial groups. In this study, we investigated whether it is feasible to attempt to prevent the spread of antibiotic resistances with a lytic bacteriophage, which can replicate in a wide range of gram-negative bacteria harbouring conjugative drug resistance-conferring plasmids. The counter-selection against the plasmid was shown to be effective, reducing the frequency of multidrug-resistant bacteria that formed via horizontal transfer by several orders of magnitude. This was true also in the presence of an antibiotic against which the plasmid provided resistance. Majority of the multiresistant bacteria subjected to phage selection also lost their conjugation capability. Overall this study suggests that, while we are obligated to maintain the selection for the spread of the drug resistances, the 'fight evolution with evolution' approach could help us even out the outcome to our favour.201324062801
4150170.9999The worldwide emergence of plasmid-mediated quinolone resistance. Fluoroquinolone resistance is emerging in gram-negative pathogens worldwide. The traditional understanding that quinolone resistance is acquired only through mutation and transmitted only vertically does not entirely account for the relative ease with which resistance develops in exquisitely susceptible organisms, or for the very strong association between resistance to quinolones and to other agents. The recent discovery of plasmid-mediated horizontally transferable genes encoding quinolone resistance might shed light on these phenomena. The Qnr proteins, capable of protecting DNA gyrase from quinolones, have homologues in water-dwelling bacteria, and seem to have been in circulation for some time, having achieved global distribution in a variety of plasmid environments and bacterial genera. AAC(6')-Ib-cr, a variant aminoglycoside acetyltransferase capable of modifying ciprofloxacin and reducing its activity, seems to have emerged more recently, but might be even more prevalent than the Qnr proteins. Both mechanisms provide low-level quinolone resistance that facilitates the emergence of higher-level resistance in the presence of quinolones at therapeutic levels. Much remains to be understood about these genes, but their insidious promotion of substantial resistance, their horizontal spread, and their co-selection with other resistance elements indicate that a more cautious approach to quinolone use and a reconsideration of clinical breakpoints are needed.200617008172
4143180.9999Mobile genes coding for efflux-mediated antimicrobial resistance in Gram-positive and Gram-negative bacteria. Efflux mechanisms that account for resistance to a variety of antimicrobial agents are commonly found in a wide range of bacteria. Two major groups of efflux systems are known, specific exporters and transporters conferring multidrug resistance (MDR). The MDR systems are able to remove antimicrobials of different classes from the bacterial cell and occasionally play a role in the intrinsic resistance of some bacteria to certain antimicrobials. Their genes are commonly located on the bacterial chromosome. In contrast, the genes coding for specific efflux systems are often associated with mobile genetic elements which can easily be interchanged between bacteria. Specific efflux systems have mainly been identified with resistances to macrolides, lincosamides and/or streptogramins, tetracyclines, as well as chloramphenicol/florfenicol in Gram-positive and Gram-negative bacteria. In this review, we focus on the molecular biology of antimicrobial resistance mediated by specific efflux systems and highlight the association of the respective resistance genes with mobile genetic elements and their distribution across species and genus borders.200313678822
4046190.9999Horizontal 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