Antimicrobial innovation by Big Pharma has slowed to a crawl while an epidemic of antimicrobial-resistant infections surges, threatening the public health. The overarching goal ofthe Wisconsin Antimicrobial Drug Discovery and Development Center is to develop therapeutic countermeasures to tackle the antimicrobial resistance crisis. Based upon our preliminary data, we hypothesize that natural product exploration of symbiotic environments using complementary cutting-edge approaches will provide a new paradigm for discovery of novel antimicrobials targeting drug resistant infections. The Center proposes innovative conceptual and technical advances to overcome critical bottlenecks identified in traditional antimicrobial drug discovery platforms. The success of this endeavor is dependent upon the ability to predict antimicrobial effectiveness ofthe symbiotic natural products in humans. The In vivo Core will assess the in vivo microbiologic effectiveness, mammalian safety, pharmacokinetics and pharmacodynamics of promising novel natural product scaffolds from each Project (1, 2, 3) in the Center. The Core uses clinically relevant murine infection models with each ofthe target, drug-resistant pathogens - fungal and gram-positive and negative bacteria. The results from these Core activities will predict which compounds with promising in vitro activity against drug-resistant pathogens are likely to progress to a clinically useful antimicrobial drug. The core services will also provide data that answer the question: which of the novel discovery approaches employed by our three CETR projects best delivers lead antimicrobial compounds. Elucidation of optimal discovery strategies will yield a transformative and sustained impact on the development of new drugs.

Public Health Relevance

There are no effective therapies for the emerging resistant pathogens that are becoming an increasing threat to the public health. The goals of the Center are to provide new, broad spectrum antimicrobial agents through a collaborative focus on high value natural product leads produced by under-explored sources of biological diversity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109673-01
Application #
8642732
Study Section
Special Emphasis Panel ()
Project Start
Project End
Budget Start
2014-04-10
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$386,016
Indirect Cost
$100,257
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Ruzzini, Antonio C; Clardy, Jon (2016) Gene Flow and Molecular Innovation in Bacteria. Curr Biol 26:R859-64
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
Zhang, Fan; Adnani, Navid; Vazquez-Rivera, Emmanuel et al. (2015) Application of 3D NMR for Structure Determination of Peptide Natural Products. J Org Chem 80:8713-9
Van Arnam, Ethan B; Ruzzini, Antonio C; Sit, Clarissa S et al. (2015) A Rebeccamycin Analog Provides Plasmid-Encoded Niche Defense. J Am Chem Soc 137:14272-4
Ramadhar, Timothy R; Zheng, Shao-Liang; Chen, Yu-Sheng et al. (2015) The crystalline sponge method: MOF terminal ligand effects. Chem Commun (Camb) 51:11252-5
Ramadhar, Timothy R; Zheng, Shao Liang; Chen, Yu Sheng et al. (2015) Analysis of rapidly synthesized guest-filled porous complexes with synchrotron radiation: practical guidelines for the crystalline sponge method. Acta Crystallogr A Found Adv 71:46-58
Sit, Clarissa S; Ruzzini, Antonio C; Van Arnam, Ethan B et al. (2015) Variable genetic architectures produce virtually identical molecules in bacterial symbionts of fungus-growing ants. Proc Natl Acad Sci U S A 112:13150-4
Wyche, Thomas P; Piotrowski, Jeff S; Hou, Yanpeng et al. (2014) Forazoline A: marine-derived polyketide with antifungal in vivo efficacy. Angew Chem Int Ed Engl 53:11583-6