A post-antibiotic era of multiple drug resistance has begun to threaten the health and well-being of mankind. A crucial limitation in economically converting untapped natural product potential to final scalable production is the lack of next-generation tools to effectively access the full medicinal impact of natural environments. This project utilizes innovative technologies to capture entire small molecule pathways and express them for the first time in E. coli, resulting in a potent pipeline of novel environmentally-derived therapeutic compounds. There are two unique components available to achieve this goal: 1) A new strain of engineered E. coli to support many of the unique building blocks needed for expression of natural product biosynthetic pathways and 2) A BAC library of 800 clones containing entire small molecule pathways up to 170 kb to be assayed for expression of anti-bacterial activities against the ESKAPE series of pathogens. The outcomes of this research are expected to significantly accelerate the discovery and production of novel antimicrobial compounds.
Public Health Relevance Statement: Public Health Relevance: This proposal is designed to accelerate the expression and discovery of environmentally-encoded complex natural products. Success will provide new antimicrobial compounds with the potential for more efficient, economical, rapid, and effective clinical translation and large-scale production.
Project Terms: Address; Anabolism; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Antifungal Agents; antimicrobial; base; Biological Assay; Biological Factors; Buffaloes; cellular engineering; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemistry; Clinical; Cloning; Collection; Complex; cost; Data; design; DNA; drug discovery; drug resistant bacteria; Engineering; Environment; Escherichia coli; Gene Expression; Genes; Genetic; Genomics; Goals; Growth; Health; High-Throughput Nucleotide Sequencing; improved; innovative technologies; interest; large scale production; Lead; Libraries; Marketing; Measurable; Metagenomics; Methods; Microbe; microbial; Multi-Drug Resistance; Natural Product Drug; next generation; novel; Outcome; Outcomes Research; pathogen; Pathway interactions; Patients; Personal Satisfaction; Procedures; Process; Production; Property; public health relevance; Reporting; screening; Sequence Analysis; Series; small molecule; Source; success; Technology; Therapeutic; Therapeutic Agents; Time; tool; Translations; Viral
