Healthcare-associated infections (HAIs) pose a tremendous threat to the personal and financial wellbeing of the American people. Over the last decade, there has been a surge in mortality due to HAIs as a result of several compounding factors (e.g., increased levels of drug resistance among microbes, escalating numbers of immunocompromised patients, and a sharp decline in the production of new antimicrobials). Consequently, there is a critical need for the development of new antifungal and antibacterial therapeutics to stem the loss of human life caused by HAIs. Unfortunately, many modern drug screening programs rely on chemically impoverished libraries that severely compromise their respective lead discovery potentials. A major shortcoming for many of these chemical libraries is the significant degree of compound homogeneity and a lack of structural novelty among their component compounds. The objective of this application is to use a chemical-epigenetics methodology to critically examine the unique secondary metabolites that are encoded by silent biosynthetic pathways in fungi as a source of novel antimicrobials. We will test the central hypothesis that the activation of silent natural-product gene clusters in fungi will provide unparalleled access to chemically diverse secondary metabolites, which we will use for procuring new antibacterial and antifungal leads. The rationale for investigating silent biosynthetic pathways for the production of antimicrobials is that secondary metabolites emerging from this source are expected to be structurally and functionally novel;thus these compounds are anticipated to have significant drug development value. Based on our research group's strong preliminary data, three specific aims have been designed to test the central hypothesis: 1) investigate the range of antimicrobial activities emerging from fungi following chemical-epigenetic modification, 2) use bioassay-guided microplate fractionation in tandem with electrospray-ionization time-of-flight mass spectrometry to dereplicate and purify bioactive natural products for testing against a panel of microbial pathogens, and 3) apply a combination of biosystematic and semisynthetic techniques to probe the structure- activity features of two unique groups of antimicrobial leads previously discovered in the PI's laboratory. This research is significant because it capitalizes on an innovative methodology, chemical epigenetics, to access cryptic natural products from fungi. These compounds represent an untapped source of bioactive organic molecules with outstanding therapeutic applications. It is anticipated that these studies will provide an array of chemically unprecedented natural products that will have superb lead development potential as part of future NIH-sponsored studies.

Public Health Relevance

These studies are designed to address the need for new antibacterial and antifungal agents for treating a wide range of microbial pathogens. This work is important because fungal secondary metabolites produced from silent biosynthetic pathways represent an untapped reservoir of chemically diverse substances that have immense potential for therapeutic development. The infusion of these structurally diverse compounds into the drug discovery pipeline is expected to have a significant positive impact on human health by providing a rich new source of novel small-molecule leads for combating a variety of bacterial and fungal illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085161-03
Application #
8204886
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
2010-01-15
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$366,432
Indirect Cost
$118,932
Name
University of Oklahoma Norman
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
848348348
City
Norman
State
OK
Country
United States
Zip Code
73019
Wang, Bin; You, Jianlan; King, Jarrod B et al. (2014) Polyketide glycosides from Bionectria ochroleuca inhibit Candida albicans biofilm formation. J Nat Prod 77:2273-9
Cai, Shengxin; King, Jarrod B; Du, Lin et al. (2014) Bioactive sulfur-containing sulochrin dimers and other metabolites from an Alternaria sp. isolate from a Hawaiian soil sample. J Nat Prod 77:2280-7
Cai, Shengxin; Du, Lin; Gerea, Alexandra L et al. (2013) Spiro fused diterpene-indole alkaloids from a creek-bottom-derived Aspergillus terreus. Org Lett 15:4186-9
You, Jianlan; Du, Lin; King, Jarrod B et al. (2013) Small-molecule suppressors of Candida albicans biofilm formation synergistically enhance the antifungal activity of amphotericin B against clinical Candida isolates. ACS Chem Biol 8:840-8
Wang, Xiaoru; You, Jianlan; King, Jarrod B et al. (2012) Waikialoid A suppresses hyphal morphogenesis and inhibits biofilm development in pathogenic Candida albicans. J Nat Prod 75:707-15
Henrikson, Jon C; Ellis, Trevor K; King, Jarrod B et al. (2011) Reappraising the structures and distribution of metabolites from black aspergilli containing uncommon 2-benzyl-4H-pyran-4-one and 2-benzylpyridin-4(1H)-one systems. J Nat Prod 74:1959-64
Cichewicz, Robert H (2010) Epigenome manipulation as a pathway to new natural product scaffolds and their congeners. Nat Prod Rep 27:11-22
Joyner, P Matthew; Liu, Jinman; Zhang, Zhijun et al. (2010) Mutanobactin A from the human oral pathogen Streptococcus mutans is a cross-kingdom regulator of the yeast-mycelium transition. Org Biomol Chem 8:5486-9
Wang, Xiaoru; Sena Filho, Jose G; Hoover, Ashley R et al. (2010) Chemical epigenetics alters the secondary metabolite composition of guttate excreted by an atlantic-forest-soil-derived Penicillium citreonigrum. J Nat Prod 73:942-8