Natural products serve as critical drugs or drug precursors with broad pharmaceutical application, including serving as the most effective antibiotics. The widespread and rapid evolution of antibiotic-resistance in pathogenic microbes makes the discovery of novel therapeutics to treat infectious diseases of urgent importance. Despite this critical need, small molecule discovery has decreased substantially in recent decades and the pipeline of new antibiotics is rapidly diminishing. The broad goals of this project are to discover novel antibiotics with high therapeutic potential by identify new natural products from insect associated Actinobacteria (aim 1), using next-generation sequencing technology and bioinformatics to help discover novel compounds from symbiotic microbes (aim 2), and evaluating the natural products discovered in SAI and SA2 for their therapeutic potential (aim 3). Through its direct integration with the multidisciplinary team in the center, the work proposed holds the promise to generate numerous new drug leads with therapeutic potential, result in a new paradigm in drug discovery, and, by translation, to impact the treatment of drug-resistant infectious diseases on a global scale.

Public Health Relevance

The emergence of antibiotic resistance in human pathogens represents a public health crisis. The goals of this project are to discover new antimicrobial drug leads from symbiotic Actinobacteria and to contribute to the development of genome-enabled approaches to drug discovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI109673-04
Application #
9235229
Study Section
Special Emphasis Panel (ZAI1-LR-M)
Project Start
Project End
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
4
Fiscal Year
2017
Total Cost
$551,928
Indirect Cost
$177,145
Name
University of Wisconsin Madison
Department
Type
Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Bratburd, Jennifer R; Keller, Caitlin; Vivas, Eugenio et al. (2018) Gut Microbial and Metabolic Responses to Salmonella enterica Serovar Typhimurium and Candida albicans. MBio 9:
Li, Hongjie; Sosa-Calvo, Jeffrey; Horn, Heidi A et al. (2018) Convergent evolution of complex structures for ant-bacterial defensive symbiosis in fungus-farming ants. Proc Natl Acad Sci U S A 115:10720-10725
Lawry, Stephanie M; Tebbets, Brad; Kean, Iain et al. (2017) Fludioxonil Induces Drk1, a Fungal Group III Hybrid Histidine Kinase, To Dephosphorylate Its Downstream Target, Ypd1. Antimicrob Agents Chemother 61:
Adnani, Navid; Braun, Doug R; McDonald, Bradon R et al. (2017) Draft Genome Sequence of Micromonospora sp. Strain WMMB235, a Marine Ascidian-Associated Bacterium. Genome Announc 5:
Matarrita-Carranza, Bernal; Moreira-Soto, Rolando D; Murillo-Cruz, Catalina et al. (2017) Evidence for Widespread Associations between Neotropical Hymenopteran Insects and Actinobacteria. Front Microbiol 8:2016
Adnani, Navid; Chevrette, Marc G; Adibhatla, Srikar N et al. (2017) Coculture of Marine Invertebrate-Associated Bacteria and Interdisciplinary Technologies Enable Biosynthesis and Discovery of a New Antibiotic, Keyicin. ACS Chem Biol 12:3093-3102
McDonald, Bradon R; Currie, Cameron R (2017) Lateral Gene Transfer Dynamics in the Ancient Bacterial Genus Streptomyces. MBio 8:
Chevrette, Marc G; Aicheler, Fabian; Kohlbacher, Oliver et al. (2017) SANDPUMA: ensemble predictions of nonribosomal peptide chemistry reveal biosynthetic diversity across Actinobacteria. Bioinformatics 33:3202-3210
Ramadhar, Timothy R; Zheng, Shao-Liang; Chen, Yu-Sheng et al. (2017) The Crystalline Sponge Method: A Solvent-Based Strategy to Facilitate Noncovalent Ordered Trapping of Solid and Liquid Organic Compounds. CrystEngComm 19:4528-4534
Zhang, Fan; Barns, Kenneth; Hoffmann, F Michael et al. (2017) Thalassosamide, a Siderophore Discovered from the Marine-Derived Bacterium Thalassospira profundimaris. J Nat Prod 80:2551-2555

Showing the most recent 10 out of 23 publications