School of Infection & Immunity

Dr Ainsley Beaton

Title: From Streptomyces to E. coli: Understanding the production and mechanism of the antivirulence compound Aurodox

Synopsis:

Enterohaemorrhagic Escherichia coli (EHEC) relies on the Type III Secretion System (T3SS) to colonise host cells and cause disease, making it an attractive target for anti-virulence approaches. Aurodox, a specialised metabolite produced by Streptomyces goldiniensis, inhibits the T3SS at sub-inhibitory concentrations and has shown protective effects in infection models. However, both its mechanism of action and its limited production titres present challenges for further development.

This work is aiming to address two main questions: “how does it works?” and the “how do we make more of it?”. On the mechanistic side, we tested whether adenylosuccinate synthase (PurA), previously proposed as the target in EPEC, is responsible for T3SS inhibition in the EHEC strain TUV93-0. Using a combination of adhesion assays, transcriptomics, secretion assays, LEE reporters in wild-type and ΔpurA strains, we found that aurodox retains full inhibitory activity even when PurA function is bypassed by adenine supplementation. This suggests that PurA is unlikely to be the primary target in this system and that aurodox may act through an alternative or context-dependent mechanism.

On the production side, we are working to overcome the low native yield of aurodox as well as investigating the possibility of generating novel molecular congeners. Using targeted engineering of the biosynthetic gene cluster to enhance flux and generate new analogues, and heterologous expression in alternative Streptomyces hosts we have demonstrated improved type three secretion system inhibition compared to commercially available aurodox.

First published: 19 August 2025

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