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  • American Society for Microbiology  (5)
  • 1
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 60, No. 8 ( 2016-08), p. 4442-4452
    Kurzfassung: Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against Trypanosoma brucei brucei . Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its in vitro antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding ( 〉 99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with T. b. rhodesiense (STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments, respectively. Spray-dried GHQ168 demonstrated exciting antitrypanosomal efficacy.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    RVK:
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2016
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 2
    In: Infection and Immunity, American Society for Microbiology, Vol. 79, No. 10 ( 2011-10), p. 3913-3921
    Kurzfassung: Some hypervirulent strains of Clostridium difficile produce the binary actin-ADP-ribosylating toxin C. difficile transferase (CDT) in addition to Rho-glucosylating toxins A and B. It has been suggested that the presence of CDT increases the severity of C. difficile -associated diseases, including pseudomembranous colitis. CDT contains a binding and translocation component, CDTb, that mediates the transport of the separate enzyme component CDTa into the cytosol of target cells, where CDTa modifies actin. Here we investigated the mechanism of cellular CDT uptake and found that bafilomycin A1 protects cultured epithelial cells from intoxication with CDT, implying that CDTa is translocated from acidified endosomal vesicles into the cytosol. Consistently, CDTa is translocated across the cytoplasmic membranes into the cytosol when cell-bound CDT is exposed to acidic medium. Radicicol and cyclosporine A, inhibitors of the heat shock protein Hsp90 and cyclophilins, respectively, protected cells from intoxication with CDT but not from intoxication with toxins A and B. Moreover, both inhibitors blocked the pH-dependent membrane translocation of CDTa, strongly suggesting that Hsp90 and cyclophilin are crucial for this process. In contrast, the inhibitors did not interfere with the ADP-ribosyltransferase activity, receptor binding, or endocytosis of the toxin. We obtained comparable results with the closely related iota-toxin from Clostridium perfringens . Moreover, CDTa and Ia, the enzyme component of iota-toxin, specifically bound to immobilized Hsp90 and cyclophilin A in vitro . In combination with our recently obtained data on the C2 toxin from C. botulinum , these results imply a common Hsp90/cyclophilin A-dependent translocation mechanism for the family of binary actin-ADP-ribosylating toxins.
    Materialart: Online-Ressource
    ISSN: 0019-9567 , 1098-5522
    RVK:
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2011
    ZDB Id: 1483247-1
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    American Society for Microbiology ; 2009
    In:  Journal of Bacteriology Vol. 191, No. 9 ( 2009-05), p. 2934-2943
    In: Journal of Bacteriology, American Society for Microbiology, Vol. 191, No. 9 ( 2009-05), p. 2934-2943
    Kurzfassung: Stenotrophomonas maltophilia is an opportunistic, highly resistant, and ubiquitous pathogen. Strains have been assigned to genogroups using amplified fragment length polymorphism. Hence, isolates of environmental and clinical origin predominate in different groups. A multilocus sequence typing (MLST) scheme was developed using a highly diverse selection of 70 strains of various ecological origins from seven countries on all continents including strains of the 10 previously defined genogroups. Sequence data were assigned to 54 sequence types (ST) based on seven loci. Indices of association for all isolates and clinical isolates of 2.498 and 2.562 indicated a significant linkage disequilibrium, as well as high congruence of tree topologies from different loci. Potential recombination events were detected in one-sixth of all ST. Calculation of the mean divergence between and within predicted clusters confirmed previously defined groups and revealed five additional groups. Consideration of the different ecological origins showed that 18 out of 31 respiratory tract isolates, including 12 out of 19 isolates from cystic fibrosis (CF) patients, belonged to genogroup 6. In contrast, 16 invasive strains isolated from blood cultures were distributed among nine different genogroups. Three genogroups contained isolates of strictly environmental origin that also featured high sequence distances to other genogroups, including the S. maltophilia type strain. On the basis of this MLST scheme, isolates can be assigned to the genogroups of this species in order to further scrutinize the population structure of this species and to unravel the uneven distribution of environmental and clinical isolates obtained from infected, colonized, or CF patients.
    Materialart: Online-Ressource
    ISSN: 0021-9193 , 1098-5530
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2009
    ZDB Id: 1481988-0
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 4
    In: mSystems, American Society for Microbiology, Vol. 6, No. 3 ( 2021-06-29)
    Kurzfassung: Understanding variation in host-associated microbial communities is important given the relevance of microbiomes to host physiology and health. Using 560 fecal samples collected from wild chimpanzees ( Pan troglodytes ) across their range, we assessed how geography, genetics, climate, vegetation, and diet relate to gut microbial community structure (prokaryotes, eukaryotic parasites) at multiple spatial scales. We observed a high degree of regional specificity in the microbiome composition, which was associated with host genetics, available plant foods, and potentially with cultural differences in tool use, which affect diet. Genetic differences drove community composition at large scales, while vegetation and potentially tool use drove within-region differences, likely due to their influence on diet. Unlike industrialized human populations in the United States, where regional differences in the gut microbiome are undetectable, chimpanzee gut microbiomes are far more variable across space, suggesting that technological developments have decoupled humans from their local environments, obscuring regional differences that could have been important during human evolution. IMPORTANCE Gut microbial communities are drivers of primate physiology and health, but the factors that influence the gut microbiome in wild primate populations remain largely undetermined. We report data from a continent-wide survey of wild chimpanzee gut microbiota and highlight the effects of genetics, vegetation, and potentially even tool use at different spatial scales on the chimpanzee gut microbiome, including bacteria, archaea, and eukaryotic parasites. Microbial community dissimilarity was strongly correlated with chimpanzee population genetic dissimilarity, and vegetation composition and consumption of algae, honey, nuts, and termites were potentially associated with additional divergence in microbial communities between sampling sites. Our results suggest that host genetics, geography, and climate play a far stronger role in structuring the gut microbiome in chimpanzees than in humans.
    Materialart: Online-Ressource
    ISSN: 2379-5077
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2021
    ZDB Id: 2844333-0
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 5
    Online-Ressource
    Online-Ressource
    American Society for Microbiology ; 2003
    In:  Antimicrobial Agents and Chemotherapy Vol. 47, No. 11 ( 2003-11), p. 3478-3484
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 47, No. 11 ( 2003-11), p. 3478-3484
    Kurzfassung: Human immunodeficiency viruses in 321 samples from tenofovir-naïve patients were retrospectively evaluated for resistance to this nucleotide analogue. All virus strains with insertions between amino acids 67 and 70 of the reverse transcriptase ( n = 6) were highly resistant. Virus strains with the Q151M mutation were divided into susceptible ( n = 12) and highly resistant ( n = 8) viruses. This difference was due to the absence or presence of the K65R mutation, which was confirmed by site-directed mutagenesis. Viral clones with various combinations of the mutations M41L, K70R, L210W, and T215F or T215Y were analyzed for cross-resistance induced by thymidine analogue mutations (TAMs). The levels of increased resistance induced by single, double, and triple mutations at the indicated positions could be ranked as follows: for mutants with single mutations, mutations at positions 41 〉 215 〉 70; for mutants with double mutations, mutations at positions 41 and 215 〉 70 and 215 = 210 and 215 〉 41 and 70; for mutants with triple mutations, mutations at positions 41, 210, and 215 〉 41, 70, and 215. Viral clones with M184V or M184I exhibited slightly increased susceptibilities to tenofovir (0.7-fold). Almost all clones with TAM-induced resistance were resensitized when M184V was present ( P 〈 0.001). Among the viruses in the clinical samples, the rate of tenofovir resistance significantly increased with the number of TAMs both in the samples with 184M and in those with 184V ( P = 0.005 and P = 0.003, respectively). A resensitizing effect of M184V was confirmed for all samples exhibiting at least one TAM ( P = 0.03). However, accumulation of at least two TAMs resulted in more than 2.0-fold reduced susceptibility to tenofovir, irrespective of the presence of M184V. Decision tree building, a classical machine learning technique, was used to generate models for the interpretation of mutations with respect to tenofovir resistance. The application of previously proposed cutoffs for a reduced response to therapy and treatment failure demonstrated the central roles of positions 215 and 65 for 1.5- and 4.0-fold reduced susceptibilities, respectively. Thus, clinically relevant resistance may be conferred by the accumulation of TAMs, and the resensitizing effect of M184V should be considered only minor.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    RVK:
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2003
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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