期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1860, 期 10, 页码 2097-2106出版社
ELSEVIER
DOI: 10.1016/j.bbagen.2016.06.025
关键词
Alteramide B; Candida albicans SC5314; Reactive oxygen species; Apoptosis; beta-Tubulin
资金
- National Key Basic Research Program of China (973 Program) [2012CB721005, 2013CB734002]
- Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scholars [31329005]
- State Key Program of the National Natural Science Foundation of China [81530091]
- NIH [R01AI097260]
- Natural Science Foundation of Shandong Province, China [ZR2013HQ048]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT13028]
- National Natural Science Funds for Distinguished Young Scholars [30325044]
Background: Alteramide B (ATB), isolated from Lysobacter enzymogenes C3, was a new polycyclic tetramate macrolactam (PTM). ATB exhibited potent inhibitory activity against several yeasts, particularly Candida albicans SC5314, but its antifungal mechanism is unknown. Methods: The structure of ATB was established by extensive spectroscopic analyses, including high-resolution mass spectrometry, ID- and 2D-NMR, and CD spectra. Flow cytometry, fluorescence microscope, transmission electron microscope, molecular modeling, overexpression and site-directed mutation studies were employed to delineate the anti-Candida molecular mechanism of ATB. Results: ATB induced apoptosis in C albicans through inducing reactive oxygen species (ROS) production by disrupting microtubules. Molecular dynamics studies revealed the binding patterns of ATB to the p-tubulin subunit. Overexpression of the wild type and site-directed mutants of the (beta-tubulin gene (TUBB) changed the sensitivity of C albicans to ATB, confirming the binding of ATB to beta-tubulin, and indicating that the binding sites are 1215, L217, L273, L274 and R282. In vivo, ATB significantly improved the survival of the candidiasis mice and reduced fungal burden. Conclusion: The molecular mechanism underlying the ATB-induced apoptosis in C. albicans is through inhibiting tubulin polymerization that leads to cell cycle arrest at the G2/M phase. The identification of ATB and the study of its activity provide novel mechanistic insights into the mode of action of PTMs against the human pathogen. General significance: This study shows that ATB is a new microtubule inhibitor and a promising anti-Candida lead compound. The results also support beta-tubulin as a potential target for anti-Candida drug discovery. (C) 2016 Elsevier B.V. All rights reserved.
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