Alteramide B is a microtubule antagonist of inhibiting Candida albicans

Yanjiao Ding, Yaoyao Li, Zhenyu Li, Juanli Zhang, Chunhua Lu, Haoxin Wang, Yuemao Shen, Liangcheng Du

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2097-2106
Number of pages10
JournalBiochimica et Biophysica Acta - General Subjects
Volume1860
Issue number10
DOIs
StatePublished - Oct 1 2016

Fingerprint

Candida
Tubulin
Candida albicans
Microtubules
Lysobacter
Pulse time modulation
Apoptosis
Lead compounds
Molecular modeling
Flow cytometry
Candidiasis
G2 Phase
Pathogens
Drug Discovery
Molecular Dynamics Simulation
Cell Cycle Checkpoints
Polymerization
Cell Division
Yeast
Mass spectrometry

Keywords

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

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Alteramide B is a microtubule antagonist of inhibiting Candida albicans. / Ding, Yanjiao; Li, Yaoyao; Li, Zhenyu; Zhang, Juanli; Lu, Chunhua; Wang, Haoxin; Shen, Yuemao; Du, Liangcheng.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1860, No. 10, 01.10.2016, p. 2097-2106.

Research output: Contribution to journalArticle

Ding, Yanjiao ; Li, Yaoyao ; Li, Zhenyu ; Zhang, Juanli ; Lu, Chunhua ; Wang, Haoxin ; Shen, Yuemao ; Du, Liangcheng. / Alteramide B is a microtubule antagonist of inhibiting Candida albicans. In: Biochimica et Biophysica Acta - General Subjects. 2016 ; Vol. 1860, No. 10. pp. 2097-2106.
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AB - 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.

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