Persons living with HIV/AIDS are vulnerable to a range of pernicious opportunistic infections and frequently succumb to the ravages of disseminated fungal disease. New drugs to treat azole-resistant fungal pathogens and refractory infections in the central nervous system are highly desirable. Marine natural products exhibit an extraordinary chemical diversity making them ideal as sources of novel hits in cultured cell assays against Candida spp., Cryptococcus sp. and other fungal pathogens. The proposal expands a successful program in discovery, structure elucidation and biological characterization of antifungal leads from marine invertebrates with emphasis on mechanism-based screens, functional assays and mechanism of action. Achievements from the past investigations have evolved into directions towards new goals, particularly methodology for discovery of antifungal agents for emergent pathogens, for example, Cryptococcus gatti, C. neoformans, and C. gatti, with emphasis on overcoming drug resistance in the melanized growth phase. Features of the technical approaches of this proposed research include refinement of powerful tools for structure elucidation at sub- micromole scale based on integration of microcryoprobe NMR, mass spectrometry, circular dichroism and organic synthesis, and a new deep-chemical diversity 'bottom-up'(DCD-BU) approach for discovery of new chemical entities. The expected results include identification of important non-azole leads for antifungal drug development, in particular against the pathogens Cryptococcus gatti and C. grubbi, with potential of beneficial outcomes in quality of life for patients living with HIV/AIDS.

Public Health Relevance

Persons living with HIV/AIDS are vulnerable to opportunistic infections induced by emergent pathogens including Cryptococcus gatti, Cryptococcus grubii, and related fluconazole-resistant Cryptococcus species. New drugs to treat azole-resistant fungal pathogens and refractory infections, particularly in the central nervous system, are highly desirable with potential beneficial outcomes in quality of life for patients living with HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI100776-02
Application #
8442243
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Xu, Zuoyu
Project Start
2012-03-15
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$364,250
Indirect Cost
$129,250
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
Widom, Julia R; Lee, Wonbae; Perdomo-Ortiz, Alejandro et al. (2013) Temperature-dependent conformations of a membrane supported zinc porphyrin tweezer by 2D fluorescence spectroscopy. J Phys Chem A 117:6171-84
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
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
Dalisay, Doralyn S; Quach, Tim; Molinski, Tadeusz F (2010) Liposomal circular dichroism. Assignment of remote stereocenters in plakinic acids K and L from a Plakortis-Xestospongia sponge association. Org Lett 12:1524-7