AIDS-related fungal infections are important targets for reduction of mortality and improvement in the quality of life for people living with AIDS. Each new generation of azole drugs, such as fluconazole, has succumbed to emergent cross resistance. Natural products are represented among clinically useful antifungal agents. Marine invertebrates, particularly Porifera (sponges), produce chemically diverse libraries of natural products, some of which possess useful antifungal activity. The general goal of this program is to find and identify small molecules from marine organisms that are active against fluconazole-resistant strains of Candida albicans and inherently fluconazole-resistant non-albicans species, including Candida glabrata and Candida krusei and use these as prototype leads for antifungal drugs. We plan to prepare and screen extracts for antifungal agents using a mechanism-selective approach that may be useful in identifying new leads for antifungal therapies. New emphases in this program are mechanism based screens and the systematic evaluation of compounds with unique mechanisms of action, including inhibition of fungal sphingolipid biosynthesis, that complement current therapies and intervene at strategic points in fungal cell metabolism or life-cycle. Active components will be isolated by a combination of solvent-partitioning, chromatography, liquid-liquid centrifugal counter current chromatography and other techniques. The in vitro antibiotic susceptibilities of pathogenic fungi will be evaluated in a panel of fluconazole-resistant fungi. Selected leads will be advanced to in vivo evaluation in murine models of Candida albicans, Cryptococcus neoformans and Candida glabrata. The structures of novel compounds will be determined by a combination of spectroscopic techniques including mass spectrometry, nuclear magnetic spectroscopy, circular dichroism and X-ray crystallography. Absolute stereochemistry of chiral molecules will be determined using a combination of chiroptical techniques and chemical degradation. Derivatives of existing leads, including the C. glabrata-specific dimeric sphingolipid, oceanapiside, will be synthesised de novo or by semi-synthetic modification to prepare limited libraries of analogs for structure-activity studies. Optimized leads identified from those libraries will be advanced to in vitro and in vivo trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039987-12
Application #
7776888
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Lambros, Chris
Project Start
1997-03-01
Project End
2012-08-31
Budget Start
2010-03-01
Budget End
2012-08-31
Support Year
12
Fiscal Year
2010
Total Cost
$348,582
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Wang, Xiao; Morinaka, Brandon I; Molinski, Tadeusz F (2014) Structures and solution conformational dynamics of stylissamides G and H from the Bahamian sponge Stylissa caribica. J Nat Prod 77:625-30
Januar, Lawrence A; Molinski, Tadeusz F (2013) Acremolin from Acremonium strictum is N(2),3-etheno-2'-isopropyl-1-methylguanine, not a 1H-azirine. Synthesis and structural revision. Org Lett 15:2370-3
Ko, Jaeyoung; Molinski, Tadeusz F (2013) D-Glucosamine-derived synthons for assembly of L-threo-sphingoid bases. Total synthesis of rhizochalinin C. J Org Chem 78:498-505
Molinski, Tadeusz F; Biegelmeyer, Renata; Stout, E Paige et al. (2013) Halisphingosines A and B, modified sphingoid bases from Haliclona tubifera. Assignment of configuration by circular dichroism and van't Hoff's principle of optical superposition. J Nat Prod 76:374-81
Molinski, Tadeusz F; Morinaka, Brandon I (2012) INTEGRATED APPROACHES TO THE CONFIGURATIONAL ASSIGNMENT OF MARINE NATURAL PRODUCTS. Tetrahedron 68:9307-9343
Stout, E Paige; Yu, Lily C; Molinski, Tadeusz F (2012) Antifungal Diterpene Alkaloids from the Caribbean Sponge Agelas citrina: Unified Configurational Assignments of Agelasidines and Agelasines. European J Org Chem 2012:5131-5135
Molinski, Tadeusz F; Reynolds, Kirk A; Morinaka, Brandon I (2012) Symplocin A, a linear peptide from the Bahamian cyanobacterium Symploca sp. Configurational analysis of N,N-dimethylamino acids by chiral-phase HPLC of naphthacyl esters. J Nat Prod 75:425-31
Stout, E Paige; Morinaka, Brandon I; Wang, Yong-Gang et al. (2012) De novo synthesis of benzosceptrin C and nagelamide H from 7-15N-oroidin: implications for pyrrole-aminoimidazole alkaloid biosynthesis. J Nat Prod 75:527-30
Dalisay, Doralyn S; Saludes, Jonel P; Molinski, Tadeusz F (2011) Ptilomycalin A inhibits laccase and melanization in Cryptococcus neoformans. Bioorg Med Chem 19:6654-7
Smith 3rd, Amos B; Hogan, Anne-Marie L; Liu, Zhuqing et al. (2011) Phorboxazole Synthetic Studies: Design, Synthesis and Biological Evaluation of Phorboxazole A and Hemi-Phorboxazole A Related Analogues. Tetrahedron 67:5069-5078

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