An antimicrobial peptidomimetic induces Mucorales cell death through mitochondria-mediated apoptosis
The incidence of mucormycosis has dramatically increased in immunocompromised patients. Moreover, the array of cellular targets whose inhibition results in fungal cell death is rather limited. Mitochondria have been mechanistically identified as central regulators of detoxification and virulence in...
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Published in | PloS one Vol. 8; no. 10; p. e76981 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
03.10.2013
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | The incidence of mucormycosis has dramatically increased in immunocompromised patients. Moreover, the array of cellular targets whose inhibition results in fungal cell death is rather limited. Mitochondria have been mechanistically identified as central regulators of detoxification and virulence in fungi. Our group has previously designed and developed a proteolytically-resistant peptidomimetic motif D(KLAKLAK)2 with pleiotropic action ranging from targeted (i.e., ligand-directed) activity against cancer and obesity to non-targeted activity against antibiotic resistant gram-negative rods. Here we evaluated whether this non-targeted peptidomimetic motif is active against Mucorales. We show that D(KLAKLAK)2 has marked fungicidal action, inhibits germination, and reduces hyphal viability. We have also observed cellular changes characteristic of apoptosis in D(KLAKLAK)2-treated Mucorales cells. Moreover, the fungicidal activity was directly correlated with vacuolar injury, mitochondrial swelling and mitochondrial membrane depolarization, intracellular reactive oxygen species accumulation (ROS), and increased caspase-like enzymatic activity. Finally, these apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine indicating mechanistic pathway specificity. Together, these findings indicate that D(KLAKLAK)2 makes Mucorales exquisitely susceptible via mitochondrial injury-induced apoptosis. This prototype may serve as a candidate drug for the development of translational applications against mucormycosis and perhaps other fungal infections. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: EMB FS DMM RP WA DPK. Performed the experiments: EMB FS DMM NA. Analyzed the data: EMB FS DMM RLS RP WA DPK. Wrote the manuscript: EMB RLS RP WA DPK. Competing Interests: The authors have declared that no competing interests exist. Current address: Center for Infectious and Inflammatory Diseases, Institute of Bioscience and Technology, Texas A&M University Health Science Center, Houston, Texas, United States of America Current address: Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, United States of America |
ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0076981 |