Update on macrolide-lincosamide-streptogramin, ketolide, and oxazolidinone resistance genes. - Related Documents




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448601.0000Update on macrolide-lincosamide-streptogramin, ketolide, and oxazolidinone resistance genes. This Minireview summarizes the changes in the field of bacterial resistance to macrolide, lincosamide, streptogramin, ketolide, and oxazolidinone (MLSKO) antibiotics since the nomenclature review in 1999. A total of 66 genes conferring resistance to this group of antibiotics has now been identified and includes 13 new rRNA methylase genes, four ATP-binding transporter genes coding for efflux proteins, and five new inactivating enzymes. During this same time period, 73 new genera carrying known rRNA methylase genes and 87 new genera carrying known efflux and/or inactivating genes have been recognized. The number of bacteria with mutations in the genes for 23S rRNA, L4 and L22 ribosomal proteins, resulting in reduced susceptibility to some members of the group of MLSKO antibiotics has also increased and now includes nine different Gram-positive and 10 different Gram-negative genera. New conjugative transposons carrying different MLSKO genes along with an increased number of antibiotics and/or heavy metal resistance genes have been identified. These mobile elements may play a role in the continued spread of the MLSKO resistance genes into new species, genera, and ecosystems.200818399991
448510.9998Distribution of macrolide, lincosamide, streptogramin, ketolide and oxazolidinone (MLSKO) resistance genes in Gram-negative bacteria. A number of different mechanisms of macrolide resistance have been described in Gram-negative bacteria. These include 16 acquired genes (esterases, phosphorylases, rRNA methylases, and effluxes) and include those thought to be unique to Gram-negative bacteria (both esterases and two of the phosphorylases) and those shared with Gram-positive bacteria (one phosphorylase) and those primarily of Gram-positive origin (rRNA methylases and efflux genes). In addition, mutations, which modify the 23S rRNA, ribosomal proteins L4 and/or L22, and/or changes in expression of innate efflux systems which occur by missense, deletion and/or insertion events have been described in five Gram-negative groups, while an innate transferase conferring resistance to streptogramin A has been identified in a sixth genus. However, the amount of information on both acquisition and mutations leading to macrolide, lincosamides, streptogramins, ketolides and oxazolidinones (MLSKO) resistance is limited. As a consequence this review likely underestimates the true distribution of acquired genes and mutations in Gram-negative bacteria. As use of these drugs increases, it is likely that interaction between members of the MLSKO antibiotic family and Gram-negative bacteria will continue to change resistance to these antibiotics; by mutations of existing genes as well as by acquisition and perhaps mutations of acquired resistant genes in these organisms and more work needs to be done to get a clearer picture of what is in the Gram-negative population now, such that changes can be monitored.200415379732
448820.9997The cfr and cfr-like multiple resistance genes. The Cfr methyl transferase causes an RNA methylation of the bacterial ribosomes impeding reduced or abolished binding of many antibiotics acting at the peptidyl transferase center. It provides multi-resistance to eight classes of antibiotics, most of which are in clinical and veterinary use. The cfr gene is found in various bacteria in many geographical locations and placed on plasmids or associated with transposons. Cfr-related genes providing similar resistance have been identified in Bacillales, and now also in the pathogens Clostridium difficile and Enterococcus faecium. In addition, the presence of the cfr gene has been detected in harbours and food markets.201829378339
447130.9997Update on acquired tetracycline resistance genes. This mini-review summarizes the changes in the field of bacterial acquired tetracycline resistance (tet) and oxytetracycline (otr) genes identified since the last major review in 2001. Thirty-eight acquired tetracycline resistant (Tc(r)) genes are known of which nine are new and include five genes coding for energy-dependent efflux proteins, two genes coding for ribosomal protection proteins, and two genes coding for tetracycline inactivating enzymes. The number of inactivating enzymes has increased from one to three, suggesting that work needs to be done to determine the role these enzymes play in bacterial resistance to tetracycline. In the same time period, 66 new genera have been identified which carry one or more of the previously described 29 Tc(r) genes. Included in the new genera is, for the first time, an obligate intracellular pathogen suggesting that this sheltered group of bacteria is capable of DNA exchange with non-obligate intracellular bacteria. The number of genera carrying ribosomal protection genes increased dramatically with the tet(M) gene now identified in 42 genera as compared with 24 and the tet(W) gene found in 17 new genera as compared to two genera in the last major review. New conjugative transposons, carrying different ribosomal protection tet genes, have been identified and an increase in the number of antibiotic resistance genes linked to tet genes has been found. Whether these new elements may help to spread the tet genes they carry to a wider bacterial host range is discussed.200515837373
442040.9997New perspectives in tetracycline resistance. Until recently, tetracycline efflux was thought to be the only mechanism of tetracycline resistance. As studies of tetracycline resistance have shifted to bacteria outside the Enterobacteriaceae, two other mechanisms of resistance have been discovered. The first is ribosomal protection, a type of resistance which is found in mycoplasmas, Gram-positive and Gram-negative bacteria and may be the most common type of tetracycline resistance in nature. The second is tetracycline modification, which has been found only in two strains of an obligate anaerobe (Bacteroides). Recent studies have also turned up such anomalies as a tetracycline efflux pump which does not confer resistance to tetracycline and a gene near the replication origin of a tetracycline-sensitive Bacillus strain which confers resistance when it is amplified.19902181236
441450.9997Macrolide resistance mechanisms in Gram-positive cocci. Two principal mechanisms of resistance to macrolides have been identified in Gram-positive bacteria. Erythromycin-resistant methylase is encoded by erm genes. Resultant structural changes to rRNA prevent macrolide binding and allow synthesis of bacterial proteins to continue. Presence of the erm gene results in high-level resistance. Modification of the mechanism whereby antibiotics are eliminated from the bacteria also brings about resistance. Bacteria carrying the gene encoding macrolide efflux (i.e. the mefE gene) display relatively low-level resistance. Azithromycin, because of its ability to achieve concentrations at sites of infections, is capable of eradicating mefE-carrying strains. Other resistance mechanisms, involving stimulation of enzymatic degradation, appear not to be clinically significant.200111574191
982760.9997Evolution of bacterial resistance to antibiotics during the last three decades. Bacterial resistance to antibiotics is often plasmid-mediated and the associated genes encoded by transposable elements. These elements play a central role in evolution by providing mechanisms for the generation of diversity and, in conjunction with DNA transfer systems, for the dissemination of resistances to other bacteria. At the University Hospital of Zaragoza, extensive efforts have been made to define both the dissemination and evolution of antibiotic resistance by studying the transferable R plasmids and transposable elements. Here we describe the research on bacterial resistance to antibiotics in which many authors listed in the references have participated. The aspects of bacterial resistance dealt with are: (i) transferable resistance mediated by R plasmids in Gram-negative bacteria, (ii) R plasmid-mediated resistance to apramycin and hygromycin in clinical strains, (iii) the transposon Tn1696 and the integron In4, (iv) expression of Escherichia coli resistance genes in Haemophilus influenzae, (v) aminoglycoside-modifying-enzymes in the genus Mycobacterium with no relation to resistance, and (vi) macrolide-resistance and new mechanisms developed by Gram-positive bacteria.199810943375
441970.9997Epidemiology of tetracycline-resistance determinants. Resistance to tetracycline is generally due either to energy-dependent efflux of tetracycline or to protection of the bacterial ribosomes from the action of tetracycline. The genes that encode this resistance are normally acquired via transferable plasmids and/or transposons. Tet determinants have been found in a wide range of Gram-positive and Gram-negative bacteria and have reduced the effectiveness of therapy with tetracycline.19947850200
483180.9997Mechanism of quinolone resistance in anaerobic bacteria. Several recently developed quinolones have excellent activity against a broad range of aerobic and anaerobic bacteria and are thus potential drugs for the treatment of serious anaerobic and mixed infections. Resistance to quinolones is increasing worldwide, but is still relatively infrequent among anaerobes. Two main mechanisms, alteration of target enzymes (gyrase and topoisomerase IV) caused by chromosomal mutations in encoding genes, or reduced intracellular accumulation due to increased efflux of the drug, are associated with quinolone resistance. These mechanisms have also been found in anaerobic species. High-level resistance to the newer broad-spectrum quinolones often requires stepwise mutations in target genes. The increasing emergence of resistance among anaerobes may be a consequence of previous widespread use of quinolones, which may have enriched first-step mutants in the intestinal tract. Quinolone resistance in the Bacteroides fragilis group strains is strongly correlated with amino acid substitutions at positions 82 and 86 in GyrA (equivalent to positions 83 and 87 of Escherichia coli). Several studies have indicated that B. fragilis group strains possess efflux pump systems that actively expel quinolones, leading to resistance. DNA gyrase seems also to be the primary target for quinolones in Clostridium difficile, since amino acid substitutions in GyrA and GyrB have been detected in resistant strains. To what extent other mechanisms, such as mutational events in other target genes or alterations in outer-membrane proteins, contribute to resistance among anaerobes needs to be further investigated.200312848726
441790.9997Genetic 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
4143100.9997Mobile 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
4418110.9997Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance. Tetracycline has been a widely used antibiotic because of its low toxicity and broad spectrum of activity. However, its clinical usefulness has been declining because of the appearance of an increasing number of tetracycline-resistant isolates of clinically important bacteria. Two types of resistance mechanisms predominate: tetracycline efflux and ribosomal protection. A third mechanism of resistance, tetracycline modification, has been identified, but its clinical relevance is still unclear. For some tetracycline resistance genes, expression is regulated. In efflux genes found in gram-negative enteric bacteria, regulation is via a repressor that interacts with tetracycline. Gram-positive efflux genes appear to be regulated by an attenuation mechanism. Recently it was reported that at least one of the ribosome protection genes is regulated by attenuation. Tetracycline resistance genes are often found on transmissible elements. Efflux resistance genes are generally found on plasmids, whereas genes involved in ribosome protection have been found on both plasmids and self-transmissible chromosomal elements (conjugative transposons). One class of conjugative transposon, originally found in streptococci, can transfer itself from streptococci to a variety of recipients, including other gram-positive bacteria, gram-negative bacteria, and mycoplasmas. Another class of conjugative transposons has been found in the Bacteroides group. An unusual feature of the Bacteroides elements is that their transfer is enhanced by preexposure to tetracycline. Thus, tetracycline has the double effect of selecting for recipients that acquire a resistance gene and stimulating transfer of the gene.19921423217
4487120.9996Detecting mutations that confer oxazolidinone resistance in gram-positive bacteria. Resistance to oxazolidinone antibiotics, including linezolid, in Gram-positive bacteria is mediated by single-nucleotide polymorphisms (SNPs) in the 23S ribosomal RNA. A G2576U change (encoded by a G2576T mutation in the rRNA genes) is found in most resistant clinical isolates of enterococci and staphylococci; a variety of changes have been found in resistant mutants selected in vitro. Pyrosequencing can be used to detect SNPs known to confer oxazolidinone resistance, including the G2576T change. Most bacteria have more than one rRNA gene copy and Pyrosequencing can also be used for allele quantification, i.e., to estimate the proportions of mutant vs wild-type alleles. The number of mutated rRNA gene copies correlates roughly with the level of oxazolidinone resistance displayed by resistant isolates. This chapter summarizes the Pyrosequencing assays that have been developed in our laboratory for analyzing oxazolidinone-resistant enterococci and staphylococci.200717185761
4474130.9996Mechanisms of resistance and resistance transfer in anaerobic bacteria: factors influencing antimicrobial therapy. The resistance of anaerobic bacteria to a number of antimicrobial agents has an impact on the selection of appropriate therapy for infections caused by these pathogens. Resistance to penicillin in Bacteroides fragilis has long been recognized. Most resistance is due to chromosomal beta-lactamases that are cephalosporinases. Two new enzymes that inactivate the ureidopenicillins and cefoxitin have been described in B. fragilis. The most common mechanisms of cefoxitin resistance is by the blocking of penetration of the drug into the periplasmic space. The transfer of beta-lactamase and penicillinase and of cefoxitin resistance has been demonstrated. Penicillin resistance in other Bacteroides is mediated by a penicillinase. Chloramphenicol resistance is mediated by a chloramphenicol acetyltransferase and by nitroreduction in anaerobic bacteria. Anaerobic bacteria are resistant to aminoglycosides because these organisms lack the oxidative transport system for intracellular drug accumulation. Metronidazole resistance, which is rarely encountered, is mediated by a decrease in nitroreduction of the compound to the active agent. Clindamycin-erythromycin resistance in B. fragilis is probably similar to macrolide-lincosamide-streptogramin resistance in aerobic bacteria. Two transfer factors, pBFTM10 and pBF4, which confer resistance to clindamycin have been described; the resistance determinant on them is widely distributed in nature. Tetracyline resistance in B. fragilis is mediated by a block in uptake of the drug. Transfer of tetracycline resistance is common; however, no transfer factor has been isolated. Transfer has been proposed to occur via a conjugal transposon. The special characteristics of the infected site influence the outcome of antimicrobial therapy, particularly in abscesses.(ABSTRACT TRUNCATED AT 250 WORDS)19846326243
4144140.9996The diversity of antimicrobial resistance genes among staphylococci of animal origin. Staphylococci of animal origin harbor a wide variety of resistance genes. So far, more than 40 different resistance genes have been identified in staphylococci from animals. This includes genes that confer resistance to virtually all classes of antimicrobial agents approved for use in animals, such as penicillins, cephalosporins, tetracyclines, macrolides, lincosamides, phenicols, aminoglycosides, aminocyclitols, pleuromutilins, and diaminopyrimidines. The gene products of some of these resistance genes confer resistance to only specific members of a 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 three major categories: (i) enzymatic inactivation, (ii) active efflux, or (iii) protection/modification/replacement of the cellular target sites of the antimicrobial agents. Mobile genetic elements, in particular plasmids and transposons, play a major role as carriers of antimicrobial resistance genes in animal staphylococci. They facilitate the exchange of resistance genes with staphylococci of human origin but also with other Gram-positive bacteria.201323499306
4416150.9996Tetracycline resistance determinants: mechanisms of action, regulation of expression, genetic mobility, and distribution. Tetracycline-resistant bacteria were first isolated in 1953 from Shigella dysenteriae, a bacterium which causes bacterial dysentery. Since then tetracycline-resistant bacterial have been found in increasing numbers of species and genera. This has resulted in reduced effectiveness of tetracycline therapy over time. Tetracycline resistance is normally due to the acquisition of new genes often associated with either a mobile plasmid or a transposon. These tetracycline resistance determinants are distinguishable both genetically and biochemically. Resistance is primarily due to either energy-dependent efflux of tetracycline or protection of the ribosomes from the action of tetracycline. Gram-negative tetracycline efflux proteins are linked to repressor proteins which in the absence of tetracycline block transcription of the repressor and structural efflux genes. In contrast, expression of the Gram-positive tetracycline efflux genes and some of the ribosomal protection genes appears to be regulated by attenuation of mRNA transcription. Specific tetracycline resistance genes have been identified in 32 Gram-negative and 22 Gram-positive genera. Tetracycline-resistant bacteria are found in pathogens, opportunistic and normal flora species. Tetracycline-resistant bacteria can be isolated from man, animals, food, and the environment. The nonpathogens in each of these ecosystems may play an important role as reservoirs for the antibiotic resistance genes. It is clear that if we are to reverse the trend toward increasingly antibiotic-resistant pathogenic bacteria we will need to change how antibiotics are used in both human and animal health and food production.19968916553
4475160.9996Clindamycin resistance in anaerobic bacteria. Knowledge of the mechanisms of antimicrobial resistance and resistance transfer in anaerobic bacteria has been gained over the past several years. There is widespread resistance to the beta-lactam antibiotics in the B. fragilis group of organisms and there is emerging penicillin resistance in other Bacteroides species. These resistances are usually mediated by chromosomal beta-lactamases. There have been two new beta-lactamases described in Bacteroides; a penicillinase which inactivates ureidopenicillins and another that inactivates cefoxitin. The transfer of the common beta-lactamase, penicillinase, and cefoxitin resistance has been documented in B. fragilis. The mechanism of tetracycline resistance in B. fragilis is the lack of accumulation of intracellular drug; the resistance is widespread in anaerobic bacteria and is seen in two-thirds of the B. fragilis strains. The transfer of tetracycline resistance is common, however, no transfer factor has yet been isolated. Clindamycin-erythromycin resistance in Bacteroides was first recognized in the mid-1970s and transferable resistance was described in 1979. The mechanism of resistance is probably similar to macrolide-lincosamide-streptinogramin-resistance seen in aerobic bacteria. Two clindamycin resistance transfer factors, pBFTM10 and pIP410 (pBF4) have been described. A common resistance determinant found both on plasmids and chromosomes is widely distributed in nature and it probably resides on a transposon. DNA homology studies indicate that there is more than one type of clindamycin resistance in Bacteroides; a newly recognized clindamycin resistance determinant is transferable. Local outbreaks of clindamycin resistance have been noted in the United States and in Europe. The susceptibility of Bacteroides in the United States in 1983 from a multi-center study reveals a 5% incidence of resistance in B. fragilis and 1% in Bacteroides species. The rate of clindamycin resistance has remained steady over the past three years in the Bacteroides fragilis group.19846598519
4830170.9996Mechanisms of resistance to quinolones. The increased use of fluoroquinolones has led to increasing resistance to these antimicrobials, with rates of resistance that vary by both organism and geographic region. Resistance to fluoroquinolones typically arises as a result of alterations in the target enzymes (DNA gyrase and topoisomerase IV) and of changes in drug entry and efflux. Mutations are selected first in the more susceptible target: DNA gyrase, in gram-negative bacteria, or topoisomerase IV, in gram-positive bacteria. Additional mutations in the next most susceptible target, as well as in genes controlling drug accumulation, augment resistance further, so that the most-resistant isolates have mutations in several genes. Resistance to quinolones can also be mediated by plasmids that produce the Qnr protein, which protects the quinolone targets from inhibition. Qnr plasmids have been found in the United States, Europe, and East Asia. Although Qnr by itself produces only low-level resistance, its presence facilitates the selection of higher-level resistance mutations, thus contributing to the alarming increase in resistance to quinolones.200515942878
9949180.9996Presence and dissemination of the multiresistance gene cfr in Gram-positive and Gram-negative bacteria. The emergence of the multiresistance gene cfr in staphylococci is of global concern. In addition to conferring resistance to phenicols, lincosamides, pleuromutilins, streptogramin A antibiotics and selected 16-membered macrolides, the cfr gene also confers resistance to the oxazolidinone linezolid. Linezolid is a last-resort antimicrobial agent for the treatment of serious infections in humans caused by resistant Gram-positive bacteria. The cfr gene is often located on plasmids and several cfr-carrying plasmids have been described, which differ in their structure, their size and the presence of additional resistance genes. These plasmids are important vehicles that promote the spread of the cfr gene not only among bacteria of the same species, but also among those of different species and genera. Moreover, the cfr gene has been identified in close proximity to different insertion sequences, which most probably also play an important role in its dissemination. This review summarizes current knowledge on the genetic environment of the multiresistance gene cfr with particular reference to mobile genetic elements and co-located resistance genes that may support its emergence.201323543608
4497190.9996Detection and expression analysis of tet(B) in Streptococcus oralis. Tetracycline resistance can be achieved through tet genes, which code for efflux pumps, ribosomal protection proteins and inactivation enzymes. Some of these genes have only been described in either Gram-positive or Gram-negative bacteria. This is the case of tet(B), which codes for an efflux pump and, so far, had only been found in Gram-negative bacteria. In this study, tet(B) was detected in two clinical Streptococcus oralis strains isolated from the gingival sulci of two subjects. In both cases, the gene was completely sequenced, yielding 100% shared identity and coverage with other previously published sequences of tet(B). Moreover, we studied the expression of tet(B) using RT-qPCR in the isolates grown with and without tetracycline, detecting constitutive expression in only one of the isolates, with no signs of expression in the other one. This is the first time that the presence and expression of the tet(B) gene has been confirmed in Gram-positive bacteria, which highlights the potential of the genus Streptococcus to become a reservoir and a disseminator of antibiotic resistance genes in an environment so prone to horizontal gene transfer as is the oral biofilm.201931448060