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Biochim Biophys Acta. 2016 Oct;1860(10):2097-106. doi: 10.1016/j.bbagen.2016.06.025. Epub 2016 Jun 29.

Alteramide B is a microtubule antagonist of inhibiting Candida albicans.

Author information

1
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
2
State Key laboratory of Microbial Technology, Shandong University, No. 27 South Shanda Road, Jinan, Shandong 250100, PR China.
3
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China; State Key laboratory of Microbial Technology, Shandong University, No. 27 South Shanda Road, Jinan, Shandong 250100, PR China. Electronic address: yshen@sdu.edu.cn.
4
State Key laboratory of Microbial Technology, Shandong University, No. 27 South Shanda Road, Jinan, Shandong 250100, PR China; Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. Electronic address: ldu3@unl.edu.

Abstract

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, 1D- 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 β-tubulin subunit. Overexpression of the wild type and site-directed mutants of the β-tubulin gene (TUBB) changed the sensitivity of C. albicans to ATB, confirming the binding of ATB to β-tubulin, and indicating that the binding sites are L215, 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 β-tubulin as a potential target for anti-Candida drug discovery.

KEYWORDS:

Alteramide B; Apoptosis; Candida albicans SC5314; Reactive oxygen species; β-Tubulin

PMID:
27373684
PMCID:
PMC4961524
DOI:
10.1016/j.bbagen.2016.06.025
[Indexed for MEDLINE]
Free PMC Article

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