Identification and distribution of a downregulatory signaling alkyloxazole in Streptomyces

Streptomyces use small molecules to dictate morphological development and secondary metabolism. Most of these signaling compounds are inducers derived from γ-butyrolactone (GBL)-synthesizing enzymes. As such, biosynthetically distinct and downregulatory signaling molecules remain understudied in Streptomyces. Here, we report the identification of alkyloxaozle (AOX, 1), a downregulator of sporulation and antibiotic production in Streptomyces. 1's structure features an oxazole head flanked by an alkyl tail synthesized by a nonribosomal peptide synthetase (NRPS) that has not been reported in Streptomyces signaling molecules. Functional studies found that 1 downregulated sporulation and secondary metabolism in several Streptomyces strains. Genome mining identified 45 homologous biosynthetic gene clusters (BGCs) only distributed in Streptomyces, underscoring the importance of AOXs to this productive genus. Altogether, this report presents a downregulatory class of signaling molecules that broadly affect Streptomyces and highlights their importance to the genus.