Characterisation of the mode of action of Aurodox, a Type III Secretion System inhibitor from Streptomyces goldiniensis

Recent work has demonstrated that the polyketide natural product Aurodox, from Streptomyces goldiniensisis able to block the pathogenesis of the murine pathogen Citrobacter rodentium. In this work we aimed to aimed gain a betterunderstanding of the mechanism of action of the compound. We show that Aurodoxdownregulates the expression of the Type Three Secretion Systems of enteropathogenic and enterohaemorhagic Escherichiacoli. Furthermore, we have used transcriptomic analysis to show that Aurodox inhibits the expression at the transcriptional level by repressing themaster regulator, ler. Our data support a model in which Aurodox acts upstream of ler and not directly on the secretion system itself. Finally, wehave shown that Aurodox, unlike some traditional antibiotics, does not induce expression of RecA, which is essential for the production of Shiga toxin. Wepropose that these properties nominate Aurodox as a promising anti-virulence therapy for the treatment of these infections.