Antibiotic resistant pathogens represent a major health issue both within the United States and around the world. For example, in the U.S., drug-resistant fungal infections and methicillin- resistant Staphlylococcus aureus (MRSA) are linked to more deaths than tuberculosis (TB) and AIDS, respectively. Further, recent genome-enabled studies have revealed that an increasing number of pathogens are evolving antibiotic resistance. There is a critical and urgent need to discover novel therapeutics to treat infectious diseases. Alarmingly, the discovery of novel natural products has decreased substantially in recent decades, in part because of pharmaceutical companies divesting from natural product research due to the perception that the most productive source for new antibiotics was depleted. This source for novel antibiotics was soil Actinobacteria in the genus Streptomyces; however, contemporary characterization of soil-derived Actinobacteria results almost entirely in the rediscovery of known compounds. Therefore, identifying new sources of microbes that produce novel biologically active small molecules is critical for maintaining public health, as is increasing the efficiency with which we identify novel natural products.
Our recent work has identified a rich, diverse, and largely untapped source of novel small molecules with therapeutic potential: Actinobacteria associated with terrestrial symbiotic systems. We have discovered 15 novel natural products from chemical characterization of 125 insect-associated Actinobacteria—a success rate of novel small molecule discovery significantly greater than the estimated 0.1% from traditional sources. Our findings further show that these insects utilize the Actinobacteria derived compounds to inhibit specialized bacterial and fungal parasites/pathogens. This selective activity argues that these insects have coevolved with symbiotic bacteria that are selected to produce biologically active small molecules. Part of the overall goal of this proposal is to fully capitalize on and validate terrestrial symbiotic Actinobacteria as candidates to become a new discovery tool for novel antibiotics.
Integration of genomic approaches to optimize identification of novel natural products has the potential to create a new paradigm in natural product-based drug discovery. To contribute to the development of genome-enabled drug discovery, the Currie lab has developed methods to integrate next-generation sequencing and bioinformatic analyses to help identify bacterial strains with high secondary metabolite potential, detect potential novel chemical space within individual strains, and to facilitate compound structural determination. Part of the overall goal of this proposal is to more fully develop and implement genomic approaches for improving the efficiency of finding novel natural products.