Understanding aurodox: A Type III secretion system inhibitor from Streptomyces goldiniensis

Aurodox, a specialised metabolite from the soil bacterium Streptomyces goldiniensis, has been shown to inhibit the Enteropathogenic Escherichia coli (EPEC) Type III Secretion System (T3SS). To further assess the utility of this molecule as an anti-virulence compound, a better understanding of its mechanism of action is required. We used whole transcriptome analysis, cell infection and GFP-reporter assays to show that Aurodox transcriptionally downregulates the expression of the Locus of Enterocyte Effacement (LEE) pathogenicity island-which encodes for the T3SS, acting via its master regulator, Ler. We have also observed similar effects across other enteric pathogens carrying a homologous T3SS such as Enterohemorrhagic Escherichia coli (EHEC). These properties suggest Aurodox may have potential for the treatment of E. coli infections of the gut. Despite the recent interest in the compound, the biosynthesis of Aurodox by Streptomyces goldiniensis is still poorly understood. To gain insight in to this, we have sequenced the whole genome of S. goldiniensis and identified a putative Aurodox biosynthetic gene cluster (BGC) which shares a high level of functional homology with the BGC encoding Kirromycin, a non-methylated Aurodox derivative. In-depth analysis of the BGC supports a model where a unique polyketide synthase pathway involving a combination of both Cis and Trans-Acyltransferases synthesise the Aurodox polyketide backbone, followed by decoration and finally the addition of a methyl group. Future work will include the heterologous expression this BGC to confirm its role in Aurodox biosynthesis, with the ultimate aim to produce novel Aurodox derivatives.