Isolating novel actinomycetes for antibiotic discovery

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DESCRIPTION (provided by applicant): An increase in the incidence of infections caused by drug resistant pathogens coupled to the need to develop antibacterial countermeasures against bioterror agents has resulted in a critical need for the development of new dual-use antibiotics. The goal of this project is to develop novel, broad-spectrum antibiotics active against bacteria of concern from a biodefense standpoint including Yersinia pestis and Bacillus anthracis as well as clinically important multi-drug-resistant bacterial pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), Acinetobacter baumannii, Enterobacteria expressing an extended-spectrum beta lactamases (ESBL) and Pseudomonas aeruginosa. This goal will be achieved by applying a new cultivation approach that utilizes a trap for the in situ capture of previously uncultured actinomycetes, the source of most antibiotics on the market today. These novel actinomycetes will then be explored for their ability to produce new antibiotics. Here we present data that demonstrates the ability of our in situ trap to: 1) efficiently enrich for actinomycetes, 2) select for different actinomycetes Genera than traditional microbiological methods and 3) isolate actinomycetes species that have not been previously discovered. In this Phase I project we will develop the trap method into a drug development pipeline and evaluate the success of this technology based on the uniqueness of the antimicrobial compounds identified from our trap-derived actinomycetes. Specific aims of the project are: Aim1: To evaluate the novelty of actinomycetes isolated by the NovoBiotic trap method, we will isolate 1000 novel actinomycetes using the trap technology and identify these species. Aim 2: To elicit antibiotic production from our 1000 trap-derived actinomycetes and prioritize 50 isolates for analytical chemistry analyses. Aim 3: To dereplicate the antibacterial compounds produced by our trap-derived Actinomycetes. The results of Phase I will be used in Phase II to develop the large-scale cultivation, fermentation, chemical dereplication of trap-derived actinomycetes necessary for the development of dual-use antibiotics. PUBLIC HEALTH RELEVANCE: Bacteria that cause infections in the community and in hospitals are becoming increasingly resistant to currently available antibiotics, so there is an urgent need for new antibiotics that will ensure public health in the years to come. The purpose of this project is to employ a new technology to discover the next generation of effective antibiotics. These antibiotics will also provide the public with a stronger defense against the threat of bioterror.