Natural product antibiotics targeting Gram-negative MDR pathogens

点击翻译按钮获取中文摘要

New antibiotics are urgently needed to combat the rise of Multi-Drug Resistance (MDR), and by far the most pressing is the identification of compounds to inhibit MDR-Gram-negative pathogens, where the treatment options for several pathogens have become severely limited.Demuris is an SME with a world-leading collection of actinomycete bacteria which are both extremely diverse and almost devoid of replicates. The collection is being used to identify and develop antibiotic and antifungal agents to combat the rise of antimicrobial resistance (AMR). Through screening >7000 diverse and dereplicated actinomycetes from the collection, Demuris has identified over 100 strains with broad-spectrum antibacterial activity that inhibit a panel of multiply antibiotic resistant E. coli strains.In this project Demuris will aim to sequence the genomes of all of these broad spectrum antibiotic producer strains. This will be performed rapidly and cheaply using long read, single molecule sequencing from Oxford-Nanopore. We will create an in-house technology platform to sequence and then bioinformatically screen the genomes of antibiotic producing bacteria at low cost using existing software. Strains bioinformatically predicted to produce known broad spectrum antibiotic compounds will be removed from the discovery pipeline, dramatically speeding up the dereplication process and zooming in rapidly on strains producing novel antibiotic compounds. Novel antibiotics will be structurally characterised and a data package consisting of microbiology and cytotoxicity will be generated. These data will be sufficient to enable evaluation for clinical development. This "data first" based approach promises to improve efficiency and will allow all resources to be prioritised on the compounds with the best chance of clinical success.