ArticleApplied and environmental microbiology2011
New nystatin-related antifungal polyene macrolides with altered polyol region generated via biosynthetic engineering of Streptomyces noursei.
Article in Applied and environmental microbiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 61 citations in OpenAlex.
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- High iron-mediated increased oral fungal burden, oral-to-gut transmission, and changes to pathogenicity ofJournal of oral microbiology · 2022Article
- Advances in Antifungal Drug Development: An Up-To-Date Mini Review.Pharmaceuticals (Basel, Switzerland) · 2021Review
- An overview of the cytochrome P450 enzymes that catalyze the same-site multistep oxidation reactions in biotechnologically relevant selected actinomycete strains.Applied microbiology and biotechnology · 2021Review
- Structural and Bioactivity Characterization of Filipin Derivatives from EngineeredAntibiotics (Basel, Switzerland) · 2020Article
- Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine.Journal of medicinal chemistry · 2019Review
- Sequential improvement of rimocidin production in Streptomyces rimosus M527 by introduction of cumulative drug-resistance mutations.Journal of industrial microbiology & biotechnology · 2019Article
- Pseudonocardia strain improvement for stimulation of the di-sugar heptaene Nystatin-like Pseudonocardia polyene B1 biosynthesis.Journal of industrial microbiology & biotechnology · 2019Article
- Improved recovery and biological activities of an engineered polyene NPP analogue in Pseudonocardia autotrophica.Journal of industrial microbiology & biotechnology · 2017Article
- Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function.Natural product reports · 2017Review
- Rare Polyene-polyol Macrolides from Mangrove-derived Streptomyces sp. ZQ4BG.Scientific reports · 2017Article
- Carboxyl-terminal domain characterization of polyene-specific P450 hydroxylase in Pseudonocardia autotrophica.Journal of industrial microbiology & biotechnology · 2016Article
- Post-PKS tailoring steps of a disaccharide-containing polyene NPP in Pseudonocardia autotrophica.PloS one · 2015Article
- CYP105-diverse structures, functions and roles in an intriguing family of enzymes in Streptomyces.Journal of applied microbiology · 2014Review
- Structure-antifungal activity relationships of polyene antibiotics of the amphotericin B group.Antimicrobial agents and chemotherapy · 2013Article
- Biosynthesis and pathway engineering of antifungal polyene macrolides in actinomycetes.Journal of industrial microbiology & biotechnology · 2013Review
- Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us?Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2013Review
- Protein engineering towards natural product synthesis and diversification.Journal of industrial microbiology & biotechnology · 2012Review
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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