Improved Antifungal Polyene Macrolides via Engineering of the Nystatin Biosynthetic Genes in Streptomyces noursei

Abstract

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.

Drug discovery and natural products: end of era or an endless frontier?

“…"post-assembly oxidation"), приводила к образованию аналогов нистатина (рис. 4) с улучшенными противогрибковыми свойствами и меньшей токсичностью [34]. Инактивация post-PKS P450, который окисляет метильную группу в нистатине до карбоксильной (по С16), сопряжённая с мутацией еноил-редуктазной активности в NysC PKS модуле, приводила к образованию метильного производного с конъюгированной гептаеновой частью (в противоположность прерванному гексаену).…”

Initiation of Polyene Macrolide Biosynthesis: Interplay between Polyketide Synthase Domains and Modules as Revealed via Domain Swapping, Mutagenesis, and Heterologous Complementation

“…1) is a medically important antifungal antibiotic, and it was recently shown that nystatin analogues with high antifungal activity and lower toxicity can be obtained via manipulation of the nystatin biosynthetic genes (7). Among the envisaged analogues that would be interesting to produce and analyze are those that would contain an extended or modified C-37 side chain resulting from the initiation of biosynthesis with a starting unit other than acetate.…”

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

“…The same compound has been synthesised by chemical modification of amphotericin B, but this approach is less efficient (Palacios et al, 2007). A nystatin heptaene counterpart of this analogue is biosynthesised at yields of 0.5 g/litre and is superior to amphotericin B in animal models of candidiasis (Brautaset et al, 2008).…”

“…This gene has been inactivated in the producers of amphotericin B, nystatin, candicidin, and rimocidin (Caffrey et al, 2008;Brautaset et al, 2008;Chen et al, 2009). In all cases, replacing the exocyclic carboxyl group with a methyl group decreases haemolytic activity but not antifungal activity.…”