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Kubanek, Julia

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    Warding Off Disease on Coral Reefs: Antimicrobial Chemical Cues and their Future in Drug Discovery
    (Georgia Institute of Technology, 2012-05-08) Kubanek, Julia
    Unlike many animals, seaweeds do not possess adaptive immune systems to ward off disease. In many cases, they produce small molecules – natural antibiotics – that prevent colonization or infection by pathogens. We have found that seaweeds produce unusual secondary metabolites against pathogen attack, including complex isoprenoid-and shikimate-derived macrolides not seen in any other organisms. Surprisingly, these natural antifungals are not distributed evenly across algal surfaces; instead they are concentrated at discrete surface patches where they provide bursts of protection at sites that may be especially vulnerable to infection due to prior wounding. Working with the Fernandez lab at Georgia Tech, we applied surface imaging mass spectrometry to intact algal surfaces to show that antifungal defenses are heterogeneously distributed, with compound concentrations high enough at localized patches to block infection. This patchy distribution may represent an optimal defense strategy, in which the most vulnerable parts of the alga are best defended. Chemical defenses of seaweeds also serve as valuable leads for pharmaceutical development. Members of one group of algal antifungal agents, the bromophycolides, exhibit potent in vitro and in vivo antimalarial activity with an unexpected mechanism of action, inhibiting growth of the malarial parasite Plasmodium falciparum at sub-micromolar concentrations. Using a molecular probe designed from the seaweed’s antifungal agent, we identified a major molecular target and drug binding mechanism within the malaria parasite that is helping guide our synthesis of novel analogs for future development.