Optimising the production of the anti-virulence compound aurodox from Streptomyces spp.

Ainsley Beaton (University of Glasgow, UK)

16:00 - 16:15 Monday 13 April Morning

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Abstract

The rise of multidrug-resistant pathogens has created an urgent need for alternative therapeutic strategies beyond traditional bactericidal antibiotics. Anti-virulence compounds, which disarm pathogens without inhibiting growth, exert reduced selective pressure and therefore show slower resistance development. Aurodox, a specialised metabolite produced by Streptomyces goldiniensis, inhibits the Type III Secretion System (T3SS) in enterohaemorrhagic Escherichia coli (EHEC) and is a promising candidate for clinical development. However, its industrial and translational potential is limited by low native production titres.  Here, we present a tripartite strategy to enhance aurodox yield: (i) media optimisation to increase precursor availability and titre; (ii) targeted editing of the biosynthetic gene cluster to improve flux, solubility and generate novel congeners; and (iii) heterologous production in alternative Streptomyces hosts. To date, media optimisation has resulted in a 4.1-fold increase in production, and preliminary BGC engineering has generated strains with improved yield and altered product profiles. Heterologous expression has also produced increased titres in some hosts and provides a platform for future chassis development.  These results establish a route towards scalable production of aurodox and support its feasibility as an anti-virulence therapeutic against T3SS-dependent pathogens. This work highlights how combining genetic, metabolic and bioprocess engineering can unlock otherwise inaccessible actinomycete metabolites for drug development.

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