The goal of this CETR center is to use a combination of innovative strategies to combat drug resistant infectious diseases. Genes that encode small molecules in bacteria have coevolved with selective environmental pressures to symbiotic hosts, such as pathways that produce protective small molecules. Taking advantage of these coevolved relationships can help guide drug discovery. This project (Project 1) will use innovative strategies to investigate the outcome of symbiosis on antimicrobial drug discovery. In particular, we will use LCMS-based untargeted metabolomics developed by us to link symbiotic natural products to niche and to drive efforts in drug discovery. To date, this approach has been highly effective, but considering the threat we now face due to drug resistant infectious diseases, a synergistic combination of expertise will be required in order to quickly identify suitable drug leads. Therefore, we will not only use metabolomics to drive discovery efforts but also combine the expertise across projects to strategically mine new sources of actinomycetes and Proteobacteria. We will take advantage of the decreasing cost of whole genome sequencing and recent advances in genomics via Project 2 to maximize our output, while utilizing the expertise of Project 3 for high content screening of interspecies interactions to stimulate growth and production of targeted bacteria. Project 1 will work closely with Core B to exploit a new paradigm in high throughput drug discovery as well as provide novel antimicrobials to Core C for in vivo evaluation. Core D will provide mechanism of action feedback, which will further drive our efforts by understanding how lead antimicrobials act. The outcome of these collaborative efforts will be suitable drug candidates to treat targeted microbial diseases.

Public Health Relevance

Currently, drug resistant infectious diseases represent the biggest threat to human health worldwide. The best source of drug leads to treat infectious diseases has been natural products. We will use co-evolved bacteria and innovative strategies to mine new sources of antibiotics and antifungal agents to combat this health threat.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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University of Wisconsin Madison
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Adnani, Navid; Rajski, Scott R; Bugni, Tim S (2017) Symbiosis-inspired approaches to antibiotic discovery. Nat Prod Rep 34:784-814
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:
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
Mevers, Emily; Chouvenc, Thomas; Su, Nan-Yao et al. (2017) Chemical Interaction among Termite-Associated Microbes. J Chem Ecol 43:1078-1085
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
Mevers, Emily; SaurĂ­, Josep; Liu, Yizhou et al. (2016) Homodimericin A: A Complex Hexacyclic Fungal Metabolite. J Am Chem Soc 138:12324-7
Lewin, Gina R; Carlos, Camila; Chevrette, Marc G et al. (2016) Evolution and Ecology of Actinobacteria and Their Bioenergy Applications. Annu Rev Microbiol 70:235-54
Ruzzini, Antonio C; Clardy, Jon (2016) Gene Flow and Molecular Innovation in Bacteria. Curr Biol 26:R859-R864
Zhang, Yan; Adnani, Navid; Braun, Doug R et al. (2016) Micromonohalimanes A and B: Antibacterial Halimane-Type Diterpenoids from a Marine Micromonospora Species. J Nat Prod 79:2968-2972
Arango, R A; Carlson, C M; Currie, C R et al. (2016) Antimicrobial Activity of Actinobacteria Isolated From the Guts of Subterranean Termites. Environ Entomol 45:1415-1423

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