Marine Biotechnology

, Volume 21, Issue 1, pp 124–137 | Cite as

DNA Binding and Molecular Dynamic Studies of Polycyclic Tetramate Macrolactams (PTM) with Potential Anticancer Activity Isolated from a Sponge-Associated Streptomyces zhaozhouensis subsp. mycale subsp. nov.

  • M. Dhaneesha
  • O. Hasin
  • K. C. Sivakumar
  • R. Ravinesh
  • C. Benjamin Naman
  • S. Carmeli
  • T. P. SajeevanEmail author
Original Article


A sponge-associated actinomycete (strain MCCB267) was isolated from a marine sponge Mycale sp. collected in the Indian Ocean off the Southeast coast of India. Phylogenetic studies of this strain using 16S rRNA gene sequencing showed high sequence similarity to Streptomyces zhaozhouensis. However, strain MCCB267 showed distinct physiological and biochemical characteristic features and was thus designated as S. zhaozhouensis subsp. mycale. subsp. nov. A cytotoxicity-guided fractionation of the crude ethyl acetate extract of strain MCCB267 culture medium yielded four pure compounds belonging to the polycyclic tetramate macrolactam (PTM) family of natural products: ikarugamycin (IK) (1), clifednamide A (CF) (2), 30-oxo-28-N-methylikarugamycin (OI) (3), and 28-N-methylikarugamycin (MI) (4). The four compounds exhibited promising cytotoxic activity against NCI-H460 lung carcinoma cells in vitro, by inducing cell death via apoptosis. Flow cytometric analysis revealed that 1, 3, and 4 induced cell cycle arrest during G1 phase in the NCI-H460 cell line, whereas 2 induced cell arrest in the S phase. A concentration-dependent accumulation of cells in the sub-G1 phase was also detected upon treatment of the cancer cell line with compounds 1–4. The in vitro cytotoxicity studies were supported by molecular docking and molecular dynamic simulation analyses. An in silico study revealed that the PTMs can bind to the minor groove of DNA and subsequently induce the apoptotic stimuli leading to cell death. The characterization of the isolated actinomycete, the study of the mode of action of the four PTMs, 1–4, and the molecular docking and molecular dynamic simulations analyses are herein described.


Streptomyces Polycyclic tetramate macrolactams Ikarugamycin Clifednamide Anticancer Apoptosis 


Funding Information

DM would like to thank the Kerala State Council for Science, Technology and Environment, Government of Kerala, India for project funding under best paper award scheme (292/2016/KSCSTE dated 7 July 2016) and Cochin University of Science and Technology and Kerala State Council for Science, Technology and Environment, Government of Kerala, India for funding.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

10126_2018_9866_MOESM1_ESM.pdf (154 kb)
Online Resource 1 Cultural characteristics of Streptomyces sp. MCCB267 on various media after 2 weeks of growth at 28 °C. (PDF 153 kb)
10126_2018_9866_MOESM2_ESM.pdf (149 kb)
Online Resource 2 Carbon source utilization pattern of Streptomyces sp. MCCB267. (PDF 148 kb)
10126_2018_9866_MOESM3_ESM.pdf (197 kb)
Online Resource 3 NMR data of the ikarugamycin derivatives 1–4. (PDF 196 kb)
10126_2018_9866_MOESM4_ESM.pdf (185 kb)
Online Resource 4 Probit regression line for the determination of IC50 of a) CF, b) OI, c) IK and d) MI on NCI-H460 cells. (PDF 184 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.National Centre for Aquatic Animal HealthCochin University of Science and TechnologyKochiIndia
  2. 2.Raymond and Beverly Sackler School of Chemistry and Faculty of Exact SciencesTel-Aviv UniversityTel-AvivIsrael
  3. 3.Bioinformatics FacilityRajiv Gandhi Centre for BiotechnologyThiruvananthapuramIndia
  4. 4.Department of Aquatic Biology and FisheriesUniversity of KeralaThiruvananthapuramIndia
  5. 5.Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research CenterNingbo UniversityNingboChina
  6. 6.Center for Marine Biotechnology and Biomedicine, Scripps Institution of OceanographyUniversity of CaliforniaLa JollaUSA

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