SARPact

Antibiotic resistance is one of the biggest threats to public health, food security, and development. While the emergence of multidrug-resistant pathogens is constantly increasing, there has been a steady decline in the discovery of new and effective antibiotics over the past years. Thus, there is an urgent need to find new antibiotics to combat drug resistances. Actinomycetes are the most important source for antibiotics as they account for up to two-thirds of all antibiotics in clinical use today. Recent advances in genome sequencing technology and large-scale bioinformatic analyses have revealed an enormous genetic potential for the production of novel natural compounds, which however is translated to the respective antibiotics under standard lab conditions. A key node to unlock this biosynthetic capacity is regulation of antibiotic biosynthesis. SARP-type transcriptional regulators are very abundant in actinomycetes, where they act as direct activators of biosynthetic gene clusters encoding different types of antibiotics. In the project SARP-act we will establish and apply a large-scale targeted process for the activation of silent biosynthetic gene clusters in actinomycetes by using SARP-type regulators. This will involve genome mining and genetic engineering of sequenced actinomycetes from the DSMZ strain collection for SARP-guided cluster activation. Engineered strains will be analyzed for the abundance of novel natural compounds with antimicrobial properties, of which lead substances will be isolated, structurally elucidated and profiled. Concomitantly, the molecular mechanistic principle of the SARPs will be investigated, which will allow for a knowledge-based optimization of the activator. SARP-act builds up upon the complementary expertise of three academic and one industrial partner, covering the fields of genetic engineering, genome mining, protein structure biology, natural compounds analytics and discovery, as well as high-throughput drug screenings.