s44hp and Hemolysis

s44hp has been researched along with Hemolysis* in 2 studies

Other Studies

2 other study(ies) available for s44hp and Hemolysis

ArticleYear
New nystatin-related antifungal polyene macrolides with altered polyol region generated via biosynthetic engineering of Streptomyces noursei.
    Applied and environmental microbiology, 2011, Volume: 77, Issue:18

    Polyene macrolide antibiotics, including nystatin and amphotericin B, possess fungicidal activity and are being used as antifungal agents to treat both superficial and invasive fungal infections. Due to their toxicity, however, their clinical applications are relatively limited, and new-generation polyene macrolides with an improved therapeutic index are highly desirable. We subjected the polyol region of the heptaene nystatin analogue S44HP to biosynthetic engineering designed to remove and introduce hydroxyl groups in the C-9-C-10 region. This modification strategy involved inactivation of the P450 monooxygenase NysL and the dehydratase domain in module 15 (DH15) of the nystatin polyketide synthase. Subsequently, these modifications were combined with replacement of the exocyclic C-16 carboxyl with the methyl group through inactivation of the P450 monooxygenase NysN. Four new polyene macrolides with up to three chemical modifications were generated, produced at relatively high yields (up to 0.51 g/liter), purified, structurally characterized, and subjected to in vitro assays for antifungal and hemolytic activities. Introduction of a C-9 hydroxyl by DH15 inactivation also blocked NysL-catalyzed C-10 hydroxylation, and these modifications caused a drastic decrease in both antifungal and hemolytic activities of the resulting analogues. In contrast, single removal of the C-10 hydroxyl group by NysL inactivation had only a marginal effect on these activities. Results from the extended antifungal assays strongly suggested that the 9-hydroxy-10-deoxy S44HP analogues became fungistatic rather than fungicidal antibiotics.

    Topics: Animals; Antifungal Agents; Biosynthetic Pathways; Candida albicans; Erythrocytes; Hemolysis; Horses; Macrolides; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Nystatin; Polyenes; Polymers; Streptomyces

2011
Improved antifungal polyene macrolides via engineering of the nystatin biosynthetic genes in Streptomyces noursei.
    Chemistry & biology, 2008, Nov-24, Volume: 15, Issue:11

    Seven polyene macrolides with alterations in the polyol region and exocyclic carboxy group were obtained via genetic engineering of the nystatin biosynthesis genes in Streptomyces noursei. In vitro analyses of the compounds for antifungal and hemolytic activities indicated that combinations of several mutations caused additive improvements in their activity-toxicity properties. The two best analogs selected on the basis of in vitro data were tested for acute toxicity and antifungal activity in a mouse model. Both analogs were shown to be effective against disseminated candidosis, while being considerably less toxic than amphotericin B. To our knowledge, this is the first report on polyene macrolides with improved in vivo pharmacological properties obtained by genetic engineering. These results indicate that the engineered nystatin analogs can be further developed into antifungal drugs for human use.

    Topics: Animals; Antifungal Agents; Base Sequence; Candida albicans; Genes, Bacterial; Genetic Engineering; Hemolysis; Humans; Male; Mice; Nystatin; Polyenes; Polymers; Streptomyces; Structure-Activity Relationship

2008
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