Macrophages and neutrophils kill the airborne fungal pathogen Aspergillus fumigatus. The dependency of this killing process on reactive oxygen intermediates (ROI) has been strongly suggested. Therefore, we investigated the enzymatic ROI detoxifying system by proteome analysis of A. fumigatus challenged by H 2 O 2 . Since many of the identified proteins and genes are apparently regulated by a putative Saccharomyces cerevisiae Yap1 homolog, the corresponding gene of A. fumigatus was identified and designated Afyap1. Nuclear localization of a functional AfYap1-eGFP fusion was stress dependent. Deletion of the Afyap1 gene led to drastically increased sensitivity of the deletion mutant against H 2 O 2 and menadione, but not against diamide and NO radicals. Proteome analysis of the ⌬Afyap1 mutant strain challenged with 2 mM H 2 O 2 indicated that 29 proteins are controlled directly or indirectly by AfYap1, including catalase 2. Despite its importance for defense against reactive agents, the Afyap1 deletion mutant did not show attenuated virulence in a murine model of Aspergillus infection. These data challenge the hypothesis that ROI such as superoxide anions and peroxides play a direct role in killing of A. fumigatus in an immunocompromised host. This conclusion was further supported by the finding that killing of A. fumigatus wild-type and ⌬Afyap1 mutant germlings by human neutrophilic granulocytes worked equally well irrespective of whether the ROI scavenger glutathione or an NADPH-oxidase inhibitor was added to the cells.In the last few decades Aspergillus fumigatus has become the most important airborne fungal pathogen of humans. Diseases caused by A. fumigatus can be divided into three categories: allergic reactions and colonization with restricted invasiveness are observed in immunocompetent individuals, while systemic infections with high mortality rates occur in immunocompromised patients. Due to the improvement in transplant medicine and the therapy of hematological malignancies, the number of cases of invasive aspergillosis has increased. Specific diagnostics are still limited, as are the possibilities of therapeutic intervention, leading to a high mortality rate of 30 to 98% for invasive aspergillosis (8). The genome of the A. fumigatus isolate Af293 was fully sequenced. It consists of a haploid set of eight chromosomes with a total size of 29.4 Mb, of which 9,926 protein-encoding sequences were identified (44). With the genome data available the regulation of genes and the expression profile of proteins of A. fumigatus can be analyzed on a global scale, including the conditions that are related to infection.The infectious agent of A. fumigatus are conidia, which are inhaled during routine daily activities (8). Therefore, in immunocompromised patients, the lung is the site of infection of A. fumigatus. In immunocompetent individuals, mucociliary clearance and phagocytic defense normally prevent the disease. Alveolar macrophages are the major resident cells of the lung alveoli; they, along with neutrophils ...

Previous studies have shown that embryonated egg provides a convenient and easy to use system for in vivo screening of anti-influenza virus inhibitors. However, it is not known whether this model is suitable for testing neuraminidase (NA) inhibitors, too. Therefore, the present study describes the evaluation of the ion-channel blockers amantadine and rimantadine in comparison with the NA inhibitors oseltamivir and zanamivir by using the influenza A virus hen's egg model. The treatment was started immediately before or after the challenge dose was placed on the chorioallantoic membrane (CAM). Differences between the survival rate of treated and untreated chick embryos infected with influenza A virus were analyzed statistically. As result, the survival rate of chick embryos could be significantly increased when the treatment with amantadine, rimantadine, oseltamivir, or zanamivir was started before the CAM was inoculated with one egg infective dose 50% (EID50) influenza A virus. When the drugs were administered shortly after viral inoculation, significant antiviral efficacy was shown for rimantadine, oseltamivir, and zanamivir. Antiviral efficacy could be demonstrated exclusively for both oseltamivir and zanamivir after the embryos were infected with higher challenge doses of 10(2) EID50 influenza A virus. In conclusion, the NA inhibitors oseltamivir and zanamivir have a significantly better antiviral activity against influenza A virus than amantadine and rimantadine tested in embryonated hen's eggs. Therefore, this model can be a valuable alternative approach for in vivo pre-testing anti-influenza virus activity of NA inhibitors.

Sanionins A (1) and B (2) were isolated from the moss Sanionia georgico-uncinata, collected on the Antarctic Livingston Island. The compounds 1 and 2 were purified by solvent extraction, silica gel column chromatography, and preparative HPLC, consecutively. The structures of the both compounds were elucidated by 1D and 2D NMR experiments and mass spectrometric investigations. These compounds showed activity against important Gram-positive pathogens, such as mycobacteria, multiresistant staphylococci, and vancomycin resistant enterococci. This activity is combined with antiinflammatoric activity and low cytotoxicity.

Antibiotics Antibiotics U 1200Hexacyclinol, a New Antiproliferative Metabolite of Panus rudis HKI 0254. -Hexacyclinol (I), an unusual, oligocyclic metabolite is discovered in cultures of the title fungal strain. The oligocyclic structure contains epoxide and endoperoxide groups, double bonds, rings, and a spherical shape. The biosynthesis of (I) occurs via the terpenoid pathway. Hexacyclinol reveals moderate antibiotic activity and strong activities as inhibitor of oxidant generation in zymosan-stimulated polymorphonuclear neutrophil leukocytes. It shows an antiproliferative effect and is moderately cytotoxic to HeLa cells. In addition, (I) exhibits moderate inhibitory activity against P. falciparum. -(SCHLEGEL, B.; HAERTL, A.; DAHSE, H.-M.; GOLLMICK, F. A.; GRAEFE*, U.; DOERFELT, H.; KAPPES, B.; J. Antibiot. 55 (2002) 9, 814-817; Hans-Knoell-Inst.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.