Biosynthetic engineering of the antifungal, anti-MRSA auroramycin

Abstract

Using an established CRISPR-Cas mediated genome editing technique for streptomycetes, we explored the combinatorial biosynthesis potential of the auroramycin biosynthetic gene cluster in Streptomyces roseosporous. Auroramycin is a potent anti-MRSA polyene macrolactam. In addition, auroramycin has antifungal activities, which is unique among structurally similar polyene macrolactams, such as incednine and silvalactam. In this work, we employed different engineering strategies to target glycosylation and acylation biosynthetic machineries within its recently elucidated biosynthetic pathway. Auroramycin analogs with variations in C-, N- methylation, hydroxylation and extender units incorporation were produced and characterized. By comparing the bioactivity profiles of five of these analogs, we determined that unique disaccharide motif of auroramycin is essential for its antimicrobial bioactivity. We further demonstrated that C-methylation of the 3, 5-epi-lemonose unit, which is unique among structurally similar polyene macrolactams, is key to its antifungal activity.

Antimicrobial potential of culturable actinobacteria isolated from the Pacific oyster Crassostrea gigas (Bivalvia, Ostreidae)

“…Polyene macrolactams have only been found in actinobacteria and have also shown a variety of activities (Skellam et al, 2013). In this regard, auroramycin, a polyene macrolactam, was produced by a strain of Streptomyces roseosporous with anti-MRSA and antifungal properties (Yeo et al, 2020). Additionally, Arai et al (2017) also found that an isomer of micromonolactam, isomicromonolactam, could be used as an enhancer of neural stem cell differentiation.…”

Discovery, characterization, and engineering of an advantageous Streptomyces host for heterologous expression of natural product biosynthetic gene clusters

“…To evaluate the biosynthetic capacity of the CH strain, we selected four heterologous polyketide BGCs producing antibiotic and anti-fungal polyketides, including the well-studied actinorhodin [44] and erythromycin [45], together with the recently discovered auroramycin [46,47] and bipentaromycin [48] (Fig. 3).…”

Modern Trends in Natural Antibiotic Discovery

“…Some of the most recent works are CRISPR/Cas-based strategies for unearthing the hidden chemical space [ 147 ]. Using a CRISPR-Cas9 gene cluster activation strategy, a unique macrolactam glycosylated by two aminosugars, auroramycin ( Figure 19 ), was isolated [ 148 , 149 ]. A transcription factor decoy strategy for targeted activation of large BGCs was reported [ 150 ].…”