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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Santa Cruz Electronic Theses and Dissertations (2013)

Natural products have a longstanding history as clinical therapeutics, making them a valuable source of biomedically-relevant research tools. This dissertation describes the application of natural products as tools for drug discovery. By covering four different research projects, this thesis will cover a renovated approach to the classical utilization of marine natural products as screening compounds for primary hit identification, and semi-synthesis for lead development.

Chapter 1 gives an overview of the current success and future challenges of natural products, with emphasis on marine-derived natural products. This chapter also includes a set of current literature examples that focus on identifying natural products with target selectivity in mind. The second chapter discusses the application of marine natural products in the discovery of antimalarials. This chapter includes the discovery and structure elucidation of the salinipostin A, a novel antimalarial chemotype with a bicyclic phosphotriester. The chapter ends with the secondary assays that were attempted to identify the mechanism of action of salinipostin A.

The third chapter describes the development of the endoperoxide merulin A for the treatment of human African trypanosomiasis. The chapter closes with site localization studies of a merulin A-derived fluorophore in order to give insight into the mechanism of action of endoperoxides against T. brucei.

Chapter 4 reports the development of a modular high-content high-throughput P. aeruginosa biofilm inhibition/dispersion screen. Assay development includes the assessment of the innate antibiotic tolerance from preformed biofilms. The results from a large scale screening campaign of a marine natural product library yield the identification of a new biofilm inhibitor skyllamycin B. The chapter ends with the evaluation of skyllamycin B and azithromycin as a co-dosing agent to eradicate preformed biofilms.

The final chapter concentrates on the identification of abyssomicin II as a latent HIV reactivating agent. This is the first example of a bacterially-derived natural product to possess latent HIV reactivating activity. While potency excludes abyssomicin II from being a lead compound, mechanistic studies reveal that abyssomicin II reactivates latent HIV through protein kinase C and histone de-acetylase independent manner. These data suggest that the mechanism of latent HIV reactivation is novel.

    Cover page: Application of Marine Natural Products: Global Health Drug Discovery, Lead Optimization, Assay Development, and Identification of Latent HIV Reactivating Agents.
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2016)
    Bioassay-guided fractionation of two marine cyanobacterial extracts using the H-460 human lung cancer cell line and the OVC-5 human ovarian cancer cell line led to the isolation of three related α-methoxy-β, β'-dimethyl-γ-pyrones each containing a modified alkyl chain, one of which was identified as the previously reported kalkipyrone and designated kalkipyrone A. The second compound was an analog designated kalkipyrone B. The third was identified as the recently reported yoshinone A, also isolated from a marine cyanobacterium. Kalkipyrone A and B were obtained from a field-collection of the cyanobacterium Leptolyngbya sp. from Fagasa Bay, American Samoa, while yoshinone A was isolated from a field-collection of cyanobacteria (cf. Schizothrix sp.) from Panama. One-dimensional and two-dimensional NMR experiments were used to determine the overall structures and relative configurations of the kalkipyrones, and the absolute configuration of kalkipyrone B was determined by (1)H NMR analysis of diastereomeric Mosher's esters. Kalkipyrone A showed good cytotoxicity to H-460 human lung cancer cells (EC50=0.9μM), while kalkipyrone B and yoshinone A were less active (EC50=9.0μM and >10μM, respectively). Both kalkipyrone A and B showed moderate toxicity to Saccharomyces cerevisiae ABC16-Monster strain (IC50=14.6 and 13.4μM, respectively), whereas yoshinone A was of low toxicity to this yeast strain (IC50=63.8μM).
      Cover page: Kalkipyrone B, a marine cyanobacterial γ-pyrone possessing cytotoxic and anti-fungal activities
      • Article
      • Peer Reviewed
      UC Santa Cruz Previously Published Works (2016)
      Biofilms are a ubiquitous feature of microbial community structure in both natural and host environments; they enhance transmission and infectivity of pathogens and provide protection from human defense mechanisms and antibiotics. However, few natural products are known that impact biofilm formation or persistence for either environmental or pathogenic bacteria. Using the combination of a novel natural products library from the fish microbiome and an image-based screen for biofilm inhibition, we describe the identification of taurine-conjugated bile acids as inhibitors of biofilm formation against both Vibrio cholerae and Pseudomonas aeruginosa. Taurocholic acid (1) was isolated from the fermentation broth of the fish microbiome-derived strain of Rhodococcus erythropolis and identified using standard NMR and MS methods. Screening of the twelve predominant human steroidal bile acid components revealed that a subset of these compounds can inhibit biofilm formation, induce detachment of preformed biofilms under static conditions, and that these compounds display distinct structure-activity relationships against V. cholerae and P. aeruginosa. Our findings highlight the significance of distinct bile acid components in the regulation of biofilm formation and dispersion in two different clinically relevant bacterial pathogens, and suggest that the bile acids, which are endogenous mammalian metabolites used to solubilize dietary fats, may also play a role in maintaining host health against bacterial infection.
        Cover page: Biofilm Formation and Detachment in Gram-Negative Pathogens Is Modulated by Select Bile Acids
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