Streptogramin

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Roland Leclercq - One of the best experts on this subject based on the ideXlab platform.

  • molecular basis of resistance to macrolides lincosamides and Streptogramins in staphylococcus saprophyticus clinical isolates
    International Journal of Antimicrobial Agents, 2011
    Co-Authors: Anne Le Bouter, Roland Leclercq, Vincent Cattoir
    Abstract:

    The aim of this study was to evaluate the prevalence of resistance to macrolide-lincosamide-Streptogramin (MLS) antibiotics as well as to assess the molecular basis of this resistance amongst 72 Staphylococcus saprophyticus urinary isolates collected from 2005 to 2009 in University Hospital of Caen (France). Of the 72 strains studied, 33 (45.8%) were resistant to at least one MLS antibiotic, including 24 (72.7%) with an M phenotype, 5 (15.2%) with an inducible MLS(B) phenotype, 3 (9.1%) with a combined M+L phenotype and 1 (3.0%) with an L phenotype. All isolates were susceptible to the combination of Streptogramins A and B. The resistance genes erm(A), erm(B), erm(C), msr(A) and lnu(A) were detected alone in 0, 0, 5 (15.2%), 24 (72.7%) and 1 (3.0%) of the 33 MLS-resistant isolates, respectively, whereas 2 strains (6.1%) were positive for both msr(A) and lnu(A). All msr(A)-positive isolates exhibited an M phenotype, whereas all five erm(C)-positive and all three lnu(A)-positive strains displayed, respectively, an inducible MLS(B) phenotype and an L phenotype with a positive Hodge test. Plasmid analysis indicated that erm(C) and lnu(A) genes were borne by small-size plasmids (ca. 2.5 kb), whereas larger plasmids (30-90 kb) harboured msr(A). In conclusion, these findings show a high prevalence of MLS resistance in S. saprophyticus, which was mainly associated with the presence of the msr(A) gene. Since S. saprophyticus colonises the gastrointestinal tract, it may constitute an unexpected reservoir for MLS resistance genes, in particular msr(A), amongst coagulase-negative staphylococci.

  • a new phenotype of resistance to lincosamide and Streptogramin a type antibiotics in streptococcus agalactiae in new zealand
    Journal of Antimicrobial Chemotherapy, 2004
    Co-Authors: Brigitte Malbruny, Anja M Werno, Trevor P Anderson, David R Murdoch, Roland Leclercq
    Abstract:

    Objectives: To characterize a new type of resistance to clindamycin in Streptococcus agalactiae. Methods: Nineteen erythromycin-susceptible, clindamycin-resistant S. agalactiae isolates from New Zealand were studied. MICs of macrolide, lincosamide and Streptogramin antibiotics were determined. Clindamycin and Streptogramin resistance genes were searched for by PCR. Isolates were compared by serotyping and by DNA macrorestriction patterns determined by PFGE. Conjugative transfer of resistance traits to recipient strains of S. agalactiae and Enterococcus faecium was assayed. Results: The 19 S. agalactiae isolates were intermediate or resistant to clindamycin (MIC range: 0.5–2 mg/L) and lincomycin (MIC range: 1–8 mg/L) and had high MICs of dalfopristin (4–32 mg/L), a Streptogramin A-type antibiotic, compared with controls. By contrast, the strains were susceptible to macrolides and quinupristin, a Streptogramin B-type antibiotic. This new phenotype was called LSA (lincosamide–Streptogramin A). Clindamycin resistance could not be transferred to recipient strains. Thirteen isolates belonged to serotype III and to a single PFGE genotype A, and five isolates belonged to serotype I and to genotype B. One isolate was non-typeable and belonged to a distinct genotype C. Conclusions: We have characterized a new LSA phenotype in S. agalactiae. Analysis of restriction patterns of S. agalactiae chromosomal DNA showed that the resistance was spread in a minimum of three bacterial clones. The genetic and biochemical basis for the resistance remains unknown.

  • Mechanisms of resistance to macrolides, lincosamides, and ketolides
    Macrolide Antibiotics, 2002
    Co-Authors: Joyce A. Sutcliffe, Roland Leclercq
    Abstract:

    Macrolide (M), lincosamide (L), Streptogramin B(SB), and ketolide (K) antibiotics are a structurally diverse group of antibiotics that have overlapping binding sites in the peptidyl transferase region of 23S rRNA. Some resistance determinants alter part of the common binding site, thereby reducing susceptibility to more than one of the MLSBK antibiotics simultaneously. The incidence of strains harboring resistance determinants to macrolide-lincosamide-Streptogramin (MLSB) antibiotics has risen, especially over the past decade. Further, the microbes have collected mobile elements that help them evade the lethal effects of antibiotics. Bacterial resistance is mounted against MLSBantibiotics on three fronts: 1) target site mutations that prevent the binding of the antibiotic to its natural cellular target (ribosome), 2) efflux of the antibiotic or alterations in the permeability barrier as a means of protection, and 3) inactivation of the antimicrobial substance. Ketolides, a novel semi-synthetic class of 14—membered macrolides, have additional binding contacts within the 50S ribosome, making them less susceptible to some of the more prevalent resistance mechanisms in pathogenic bacteria.

  • Resistance to Quinupristin-Dalfopristin Due to Mutation of L22 Ribosomal Protein in Staphylococcus aureus
    Antimicrobial agents and chemotherapy, 2002
    Co-Authors: Brigitte Malbruny, Bruno Fantin, Annie Canu, Bülent Bozdogan, Virginie Zarrouk, Sylvie Dutka-malen, Celine Feger, Roland Leclercq
    Abstract:

    The mechanism of resistance to the Streptogramin antibiotics quinupristin and dalfopristin was studied in a Staphylococcus aureus clinical isolate selected under quinupristin-dalfopristin therapy, in four derivatives of S. aureus RN4220 selected in vitro, and in a mutant selected in a model of rabbit aortic endocarditis. For all strains the MICs of erythromycin, quinupristin, and quinupristin-dalfopristin were higher than those for the parental strains but the MICs of dalfopristin and lincomycin were similar. Portions of genes for domains II and V of 23S rRNA and the genes for ribosomal proteins L4 and L22 were amplified and sequenced. All mutants contained insertions or deletions in a protruding β hairpin that is part of the conserved C terminus of the L22 protein and that interacts with 23S rRNA. Susceptible S. aureus RN4220 was transformed with plasmid DNA encoding the L22 alteration, resulting in transformants that were erythromycin and quinupristin resistant. Synergistic ribosomal binding of Streptogramins A and B, studied by analyzing the fluorescence kinetics of pristinamycin I A -ribosome complexes, was abolished in the mutant strain, providing an explanation for quinupristin-dalfopristin resistance.

  • Effects of genes encoding resistance to Streptogramins A and B on the activity of quinupristin-dalfopristin against Enterococcus faecium.
    Antimicrobial agents and chemotherapy, 1999
    Co-Authors: Bülent Bozdogan, Roland Leclercq
    Abstract:

    In recent years, enterococci have become one of the most common causes of nosocomial infections, while certain strains have acquired resistance to all available antimicrobial agents, including aminoglycosides, penicillins, and glycopeptides. Quinupristin-dalfopristin is an antimicrobial combination developed for the treatment of infections due to vancomycin-resistant Enterococcus faecium (20). This antimicrobial belongs to the Streptogramin class which includes naturally synthesized antibiotics composed of two chemically distinct factors, Streptogramins A (SA) and Streptogramins B (SB). Quinupristin-dalfopristin is a semisynthetic injectable Streptogramin mixture of quinupristin (SB) and dalfopristin (SA) in a 30:70 ratio (9). Binding of these factors to the 50S ribosomal subunit causes inhibition of protein synthesis (37). Alone, each factor has a moderate bacteriostatic activity, but in combination, they often display a bactericidal synergistic effect (9). This is related to the synergistic binding of the factors to their ribosomal target site. Each factor binds a different site on the peptidyltransferase domain of the ribosome, but the binding of SA causes a conformational change which increases the affinity of SB for its target (36). Since SA and SB are chemically unrelated and have different binding sites, the mechanisms of resistance to these two Streptogramin types are different. In E. faecium, an acetyltransferase encoded by the satA gene inactivates Streptogramins A (31). After completion of this work, a new satG gene encoding a putative acetyltransferase which appeared to be prevalent in E. faecium was reported (39). Both genes are related to the acetyltransferase genes vat (7), vatB (2), and vatC (4) reported in staphylococci. Resistance to Streptogramins B is due either to hydrolysis of the antibiotic mediated by the vgb gene (12, 23) initially reported in Staphylococcus aureus (6) or to modification of the ribosomal target by a 23S rRNA methylase encoded by the ermB gene (24, 38). Other staphylococcal genes such as vga and vgaB conferring resistance to SA by a putative efflux mechanism (3, 5) or msrA encoding a protein which participates in the active efflux of macrolides and SB (34) have not been reported in enterococci. Because of the synergism displayed by the two Streptogramin types, it has been suggested that acquisition of isolated resistance to dalfopristin or quinupristin could have no or only partial negative impact on the antimicrobial activity of the combination (13, 25). In fact, it has been shown that inhibitory synergy between the two factors is maintained in vitro against E. faecium strains resistant to quinupristin by synthesis of a ribosomal methylase (19). However, the consequences of inactivation of dalfopristin or quinupristin or the outcome of combined mechanisms of resistance on the activity of quinupristin-dalfopristin have not been systematically analyzed. We have studied the activity of quinupristin-dalfopristin against 45 clinical strains of E. faecium isolated from patients in different French hospitals in relation to the mechanisms of resistance to quinupristin and dalfopristin. Recombinant plasmids containing the three Streptogramin resistance genes well characterized in enterococci, ermB, satA, and vgb alone or in all possible combinations, were also constructed. The plasmids were introduced into E. faecium and S. aureus to evaluate the impact of the various resistance mechanisms on the activity of quinupristin-dalfopristin.

Wolfgang Witte - One of the best experts on this subject based on the ideXlab platform.

  • methicillin resistant and susceptible staphylococcus aureus strains of clonal lineages st398 and st9 from swine carry the multidrug resistance gene cfr
    Antimicrobial Agents and Chemotherapy, 2009
    Co-Authors: Corinna Kehrenberg, Stefan Schwarz, Christiane Cuny, Birgit Strommenger, Wolfgang Witte
    Abstract:

    Methicillin-resistant Staphylococcus aureus clonal lineage ST398 and methicillin-susceptible lineage ST9 strains have their main reservoir in swine but can colonize and cause infections in humans. The phenicol/lincosamide/oxazolidinone/pleuromutilin/Streptogramin A multidrug resistance gene cfr was detected in isolates of both clonal lineages, rendering a spread to humans with exposure to swine farming possible.

  • occurrence and spread of antibiotic resistances in enterococcus faecium
    International Journal of Food Microbiology, 2003
    Co-Authors: Ingo Klare, Guido Werner, Carola Konstabel, Dietlinde Badstubner, Wolfgang Witte
    Abstract:

    Enterococci are the second to third most important bacterial genus in hospital infections. Especially Enterococcus (E.) faecium possesses a broad spectrum of natural and acquired antibiotic resistances which are presented in detail in this paper. From medical point of view, the transferable resistances to glycopeptides (e.g., vancomycin, VAN, or teicoplanin, TPL) and Streptogramins (e.g., quinupristin/dalfopristin, Q/D) in enterococci are of special interest. The VanA type of enterococcal glycopeptide resistance is the most important one (VAN-r, TPL-r); its main reservoir is E. faecium. Glycopeptide-resistant E. faecium (GREF) can be found in hospitals and outside of them, namely in European commercial animal husbandry in which the glycopeptide avoparcin (AVO) was used as growth promoter in the past. There are identical types of the vanA gene clusters in enterococci from different ecological origins (faecal samples of animals, animal feed, patients in hospitals, persons in the community, waste water samples). Obviously, across the food chain (by GREF-contaminated meat products), these multiple-resistant bacteria or their vanA gene clusters can reach humans. In hospital infections, widespread epidemic-virulent E. faecium isolates of the same clone with or without glycopeptide resistance can occur; these strains often harbour different plasmids and the esp gene. This indicates that hospital-adapted epidemic-virulent E. faecium strains have picked up the vanA gene cluster after they were already widely spread. The Streptogramin virginiamycin was also used as feed additive in commercial animal husbandry in Europe for more than 20 years, and it created reservoirs for Streptogramin-resistant E. faecium (SREF). In 1998/1999, SREF could be isolated in Germany from waste water of sewage treatment plants, from faecal samples and meat products of animals that were fed virginiamycin (cross resistance to Q/D), from stools of humans in the community, and from clinical samples. These isolations of SREF occurred in a time before the Streptogramin combination Q/D was introduced for therapeutic purposes in German hospitals in May 2000, while other Streptogramins were not used in German clinics. This seems to indicate that the origin of these SREF or their Streptogramin resistance gene(s) originated from other sources outside the hospitals, probably from commercial animal husbandry. In order to prevent the dissemination of multiple antibiotic-resistant enterococci or their transferable resistance genes, a prudent use of antibiotics is necessary in human and veterinary medicine, and in animal husbandry.

  • multiplex pcr assay for simultaneous detection of nine clinically relevant antibiotic resistance genes in staphylococcus aureus
    Journal of Clinical Microbiology, 2003
    Co-Authors: Birgit Strommenger, Guido Werner, Christiane Kettlitz, Wolfgang Witte
    Abstract:

    In this study we describe a multiplex PCR assay for the detection of nine clinically relevant antibiotic resistance genes of Staphylococcus aureus. Conditions were optimized to amplify fragments of mecA (encoding methicillin resistance), aacA-aphD (aminoglycoside resistance), tetK, tetM (tetracycline resistance), erm(A), erm(C) (macrolide-lincosamide-Streptogramin B resistance), vat(A), vat(B), and vat(C) (Streptogramin A resistance) simultaneously in one PCR amplification. An additional primer pair for the amplification of a fragment of the staphylococcal 16S rDNA was included as a positive control. The multiplex PCR assay was evaluated on 30 different S. aureus isolates, and the PCR results correlated with the phenotypic antibiotic resistance data obtained by the broth microdilution assay. The multiplex PCR assay offers a rapid, simple, and accurate identification of antibiotic resistance profiles and could be used in clinical diagnosis as well as for the surveillance of the spread of antibiotic resistance determinants in epidemiological studies.

  • intra hospital dissemination of quinupristin dalfopristin and vancomycin resistant enterococcus faecium in a paediatric ward of a german hospital
    Journal of Antimicrobial Chemotherapy, 2003
    Co-Authors: Guido Werner, Ingo Klare, Friedrichbernhard Spencker, Wolfgang Witte
    Abstract:

    Objectives: To demonstrate nosocomial transmission of Enterococcus faeclum resistant to quinupristin/ dalfopristin and vancomycin/teicoplanin among paediatric patients in a German hospital ward. Materials and methods: Multiply-resistant E. faecium were isolated from three female patients aged 9 months, 2 and 15 years during a 10 day time span. Antibiotic susceptibilities were determined by microbroth dilution. Clonal relatedness among the isolates was investigated via Smal-macrorestriction analysis by PFGE, multilocus sequence typing (MLST), and plasmid profiling. Presence of virulence and resistance determinants was tested by polymerase chain reaction (PCR). Selected resistance genes were localized by Southern hybridizations. Results: A single E. faecium Isolate per patient was investigated. All exhibited resistances to quinupristin/ dalfopristin, vancomycin/teicoplanin, streptomycin (high-level), penicillin/ampicillin, erythromycin, oxytetracycline, chloramphenicol, rifampicin and fusidic acid. The isolates were susceptible to linezolid only and intermediately resistant to fluoroquinolones Including moxifloxacin. PFGE revealed identical patterns for all three Isolates. PCRs for virulence determinants hyaluronidase and enterococcal surface protein, esp, were negative, whereas PCR for the enterocin A gene was positive. MLST identified clonal type [8-5-1-1-1-1-1] belonging to a clonal subgroup C1 of hospital- and outbreak-related E. faecium. Southern hybridizations located several resistance genes (erm(B), va(D), vanA) on a large plasmid, which was transferable in mating experiments with an E. faecium recipient. Conclusions: These data show routes of dissemination of resistance to multiple antibiotics including Streptogramins and glycopeptides in E. faecium via vertical and/or horizontal gene transfer. The isolates spread in the absence of a direct selective pressure, as none of the patients had received earlier Streptogramin or glycopeptide therapy.

  • methicillin resistant quinupristin dalfopristin resistant staphylococcus aureus with reduced sensitivity to glycopeptides
    Journal of Clinical Microbiology, 2001
    Co-Authors: Guido Werner, C Cuny, Franzjosef Schmitz, Wolfgang Witte
    Abstract:

    Of 3,052 Staphylococcus aureus strains collected by the European SENTRY surveillance study, 35 were found to be nonsusceptible to quinupristin-dalfopristin (MIC of ≥2 mg/liter). These isolates originated from four hospitals in France and one in Spain. In isolates from two Parisian hospitals exhibiting the same SmaI macrorestriction pattern, Streptogramin resistance was based on vatA and vgbA. One isolate from a hospital in Lyon and 22 from a hospital in Lille were of the vatB vgaB Streptogramin A resistance genotype and possessed ermA and/or ermC. As deduced from the loss of either Streptogramin A or Streptogramin B resistance determinants in particular isolates, resistance to quinupristin-dalfopristin requires mechanisms conferring resistance to both compounds. The SmaI macrorestriction patterns of strains from hospitals in Lille and Lyon were different; however, similarity analysis suggested a relatedness of 20 methicillin-resistant S. aureus strains from the Lille hospital, a finding confirmed by PCR typing based on three different genomic polymorphisms. These groups of isolates were found to be hetero-glycopeptide-intermediate susceptible S. aureus. Information about the failure of glycopeptide chemotherapy has not been available.

A L Barry - One of the best experts on this subject based on the ideXlab platform.

Martin Fussenegger - One of the best experts on this subject based on the ideXlab platform.

  • Streptogramin and tetracycline responsive dual regulated expression of p27kip1 sense and antisense enables positive and negative growth control of chinese hamster ovary cells
    Nucleic Acids Research, 2001
    Co-Authors: Cornelia Fux, Samuel Moser, Stefan Schlatter, Markus Rimann, James E Bailey, Martin Fussenegger
    Abstract:

    We constructed a dual regulated expression vector cassette (pDuoRex) whereby two heterologous genes can be independently regulated via Streptogramin- and tetracycline-responsive promoters. Two different constructs containing growth-promoting and growth-inhibiting genes were stably transfected in recombinant Chinese hamster ovary (CHO) cells that express the Streptogramin- and tetracycline-dependent transactivators in a dicistronic configuration. An optimally balanced heterologous growth control scenario was achieved by reciprocal expression of the growth-inhibiting human cyclin-dependent kinase inhibitor p27Kip1 in sense (p27Kip1S) and antisense (p27Kip1AS) orientation. Exclusive expression of p27Kip1S resulted in complete G1-phase-specific growth arrest, while expression of only p27Kip1AS showed significantly increased proliferation compared to control cultures (both antibiotics present), presumably by decreasing host cell p27Kip1 expression. In a second system, a derivative of pDuoRex encoding Streptogramin-responsive expression of the growth-promoting SV40 small T antigen (sT) and tetracycline-regulated expression of p27Kip1 was stably transfected into CHO cells. Expression of sT alone resulted in an increase in cell proliferation, but the expression of p27Kip1 failed to provide the expected G1-specific growth arrest despite having demonstrated expression of the protein. This illustrates the difficulty in balancing the complex pathways underlying cell proliferation control through the expression of two functionally distinct genes involved in those pathways, and how a single-gene sense/antisense approach using pDuoRex can overcome this barrier to complete metabolic engineering control.

Ada Yonath - One of the best experts on this subject based on the ideXlab platform.

  • Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the Streptogramins dalfopristin and quinupristin
    BMC Biology, 2004
    Co-Authors: Jörg M Harms, Frank Schlünzen, Paola Fucini, Heike Bartels, Ada Yonath
    Abstract:

    Background The bacterial ribosome is a primary target of several classes of antibiotics. Investigation of the structure of the ribosomal subunits in complex with different antibiotics can reveal the mode of inhibition of ribosomal protein synthesis. Analysis of the interactions between antibiotics and the ribosome permits investigation of the specific effect of modifications leading to antimicrobial resistances. Streptogramins are unique among the ribosome-targeting antibiotics because they consist of two components, Streptogramins A and B, which act synergistically. Each compound alone exhibits a weak bacteriostatic activity, whereas the combination can act bactericidal. The Streptogramins A display a prolonged activity that even persists after removal of the drug. However, the mode of activity of the Streptogramins has not yet been fully elucidated, despite a plethora of biochemical and structural data. Results The investigation of the crystal structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with the clinically relevant Streptogramins quinupristin and dalfopristin reveals their unique inhibitory mechanism. Quinupristin, a Streptogramin B compound, binds in the ribosomal exit tunnel in a similar manner and position as the macrolides, suggesting a similar inhibitory mechanism, namely blockage of the ribosomal tunnel. Dalfopristin, the corresponding Streptogramin A compound, binds close to quinupristin directly within the peptidyl transferase centre affecting both A- and P-site occupation by tRNA molecules. Conclusions The crystal structure indicates that the synergistic effect derives from direct interaction between both compounds and shared contacts with a single nucleotide, A2062. Upon binding of the Streptogramins, the peptidyl transferase centre undergoes a significant conformational transition, which leads to a stable, non-productive orientation of the universally conserved U2585. Mutations of this rRNA base are known to yield dominant lethal phenotypes. It seems, therefore, plausible to conclude that the conformational change within the peptidyl transferase centre is mainly responsible for the bactericidal activity of the Streptogramins and the post-antibiotic inhibition of protein synthesis.

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