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Published on: February 14, 2018
Iturin A disrupts Cryptococcus neoformans membrane integrity, attenuates virulence, and synergizes with amphotericin
Yehia Elgammal1, Rafael I Garcia Martinez1, Claudia L Charles-Niño1
1Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL USA.
Abstract:
Cryptococcus neoformans is a major fungal pathogen with severely limited therapeutic options. We evaluated the antifungal activity of the lipopeptide iturin A against eight clinical isolates of C. neoformans. Iturin A exhibited robust anti-cryptococcal activity, with minimum inhibitory concentrations ranging from 12.5 to 25 μg/mL, and demonstrated minimal toxicity in A549 lung epithelial cells and HepG2/C3A liver cells. Combination treatment with amphotericin B was synergistic (fractional inhibitory concentration index, 0.37). Mechanistic analyses showed that iturin A disrupts cryptococcal membrane integrity and induces intracellular reactive oxygen species accumulation, leading to fungal cell death. Iturin A also reduced biofilm formation and impaired capsule production. In the Caenorhabditis elegans infection model, treatment with iturin A alone or in combination with amphotericin B prolonged host survival and reduced fungal burden. Although iturin A decreased cryptococcal phagocytosis by J774 macrophage- and NR-9460 microglia-like cells, it enhanced intracellular killing by these phagocytes. Collectively, these findings demonstrate that iturin A exhibits multifaceted activity against C. neoformans through membrane disruption, oxidative stress induction, and interference with virulence determinants, supporting its potential as a novel anti-cryptococcal therapeutic agent.
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