Medicinal Chemistry Research

, Volume 26, Issue 11, pp 2751–2760 | Cite as

RETRACTED ARTICLE: Rhodozepinone, a new antitrypanosomal azepino-diindole alkaloid from the marine sponge-derived bacterium Rhodococcus sp. UA13

  • Yasmin Elsayed
  • John RefaatEmail author
  • Usama R. Abdelmohsen
  • Safwat Ahmed
  • Mostafa A. Fouad
Original Research


A new azepino-diindole alkaloid; rhodozepinone (1), along with five known compounds, including 2-amino-3-[2(1H)-quinolinon-4-yl]propionic acid (2), 3-hydroxy-2-methyl-4H-pyran-4-one (maltol) (3), phenyl acetic acid methyl ester (4), indole-3-acetic acid (5), and 2-amino-3-(1H-indol-3-yl) propanoic acid (tryptophan) (6) were isolated and identified from the broth culture of Rhodococcus sp. UA13, which had been previously recovered from the Red Sea sponge Callyspongia aff. Implexa. The structures of compounds (16) were determined by spectroscopic analyses, including 1D and 2D NMR experiments in combination with HR-ESI-MS, as well as comparison with the literature. All the characterized metabolites were firstly reported herein from this marine sponge-associated actinomycete, and among them, (3), (4), and (6) were characterized for the first time from the genus Rhodococcus, whereas this is the first report for isolation of compound (2) from a natural source. Moreover, both the antimicrobial and antitrypanosomal properties of the isolated metabolites (16) were evaluated, and only rhodozepinone (1) exhibited significant antibacterial and antitrypanosomal activities against Staphylococcus aureus NCTC 8325 (IC50 = 8.9 µg/ml) and Trypanosoma brucei brucei TC221 [IC50 = 16.3 (48 h) and 11.8 (72 h) µg/ml], respectively. These results totally reflected the potential of sponge-derived actinomycetes as a rich source of new natural products with interesting bioactivities, as well as their promising future contribution to drug discovery.


Actinomycetes Antibacterial Antitrypanosomal Azepino-diindole Rhodococcus Rhodozepinone 



The authors are grateful to Dr. Matthias Grüne for the NMR data acquisition. Our thanks also to Antje Fuss/ Prof. August Stich (SFB 630 TP Z1, University of Würzburg) for the antimicrobial and antitrypanosomal assays.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1974_MOESM1_ESM.docx (7.4 mb)
Supplementary Information


  1. Abdelmohsen UR, Balasubramanian S, Oelschlaeger TA, Grkovic T, Pham NB, Quinn RJ, Hentschel U (2017) Potential of marine natural products against drug-resistant fungal, viral, and parasitic infections. Lancet Infect Dis 17:e30–e41CrossRefPubMedGoogle Scholar
  2. Abdelmohsen UR, Bayer K, Hentschel U (2014) Diversity, abundance and natural products of marine sponge-associated actinomycetes. Nat Prod Rep 31:381–399CrossRefPubMedGoogle Scholar
  3. Abdelmohsen UR, Pimentel-Elardo SM, Hanora A, Radwan M, Abou-El-Ela SH, Ahmed S, Hentschel U (2010) Isolation, phylogenetic analysis and anti-infective activity screening of marine sponge-associated actinomycetes. Mar Drugs 8:399–412CrossRefPubMedPubMedCentralGoogle Scholar
  4. Abdelmohsen UR, Szesny M, Othman EM, Schirmeister T, Grond S, Stopper H, Hentschel U (2012) Antioxidant and anti-protease activities of diazepinomicin from the sponge-associated Micromonospora strain RV115. Mar Drugs 10:2208–2221CrossRefPubMedPubMedCentralGoogle Scholar
  5. Andayani DS, Sukandar E, Adnyani K (2014) Isolation, identification of phenyl acetic acid from Streptomyces galbus TP2 strain and its toxicity. Int. J Pharm Pharm Sci 6:643–646Google Scholar
  6. Ashelford KE, Chuzhanova NA, Fry JC, Jones AJ, Weightman AJ (2006) At least 1 in 20 16S rRNA sequence records currently held in public repositories is estimated to contain substantial anomalies. Appl Environ Microbiol 71:7724–7736CrossRefGoogle Scholar
  7. Cheng C, Othman EM, Reimer A, Grune M, Kozjak-Pavlovic V, Stopper H, Hentschel U, Abdelmohsen UR (2016) Ageloline, A new antioxidant and antichlamydial quinolone from the marine sponge-derived bacterium Streptomyces sp SBT345. Tetrahedron Lett 57:2786–2789CrossRefGoogle Scholar
  8. de Candia M, Zaetta G, Denora N, Tricarico D, Majellaro M, Cellamare S, Altomare CD (2017) New azepino[4,3-b]indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity. Eur J Med Chem 125:288–298CrossRefPubMedGoogle Scholar
  9. Eltamany EE, Abdelmohsen UR, Ibrahim AK, Hassanean HA, Hentschel U, Ahmed SA (2014) A new antibacterial xanthone from the marine sponge-derived Micrococcus sp. EG45. Bioorg Med Chem Lett 24:4939–4942CrossRefPubMedGoogle Scholar
  10. Evidente A, Iacobellis NS, Sisto A (1993) Isolation of indole-3-acetic acid methyl ester, a metabolite of indole-3-acetic acid from Pseudomonas amygdali. Experientia 49:182–183CrossRefGoogle Scholar
  11. Grkovic T, Abdelmohsen UR, Othman EM, Stopper H, Edrada-Ebel R, Hentschel U, Quinn RJ (2014) Two new antioxidant actinosporin analogs from the calcium alginate beads culture of sponge-associated Actinokineospora sp. strain EG49. Bioorg Med Chem Lett 24:5089–5092CrossRefPubMedGoogle Scholar
  12. Hentschel U, Schmid M, Wagner M, Fieseler L, Gernert C, Hacker J (2001) Isolation and phylogenetic analysis of bacteria with antimicrobial activities from the mediterranean sponges Aplysina aerophoba and Aplysina cavernicola. FEMS Microbiol Ecol 35:305–312CrossRefPubMedGoogle Scholar
  13. Holland J, Gooding D, Chorlton A (2014) Novel rebamipide complexes and cocrystals. US Patent 20140039005 A1, filled February 24, 2012, issued February 24, 2014Google Scholar
  14. Huber W, Koella JC (1993) A comparison of three methods of estimating ec50 in studies of drug resistance of malaria parasites. Acta Trop 55:257–261CrossRefPubMedGoogle Scholar
  15. Ibrahim MA, Aliyu AB, Abdullahi H, Solomon T, Toko E, Garba A, Bashir M, Habila N (2013) Lactone-rich fraction from Vernonia blumeoides: antitrypanosomal activity and alleviation of the parasite-induced anemia and organ damage. J Nat Med 67:750–757CrossRefPubMedGoogle Scholar
  16. Inderlied CB, Salfinger M (1995) Antimicrobial agents and susceptibility tests: Mycobacteria. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH (ed) Manual of clinical microbiology, 6th ed. American Society for Microbiology, Washington DC, p 1385–1404Google Scholar
  17. Jacobs RT, Nare B, Phillips MA (2011) State of the art in African trypanosome drug discovery. Curr Top Med Chem 11:1255–1274CrossRefPubMedPubMedCentralGoogle Scholar
  18. Kali A (2015) Antibiotics and bioactive natural products in treatment of methicillin resistant Staphylococcus aureus: a brief review. Pharmacogn Rev 9:29–34CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kim J (2009) Understanding the evolution of methicillin-resistant Staphylococcus aureus. Clin Microbiol Newsl 31:17–23CrossRefGoogle Scholar
  20. Kornsakulkarn J, Saepua S, Supothina S, Chanthaket R, Thongpanchang C (2014) Sporaridin and sporazepin from actinomycete Streptosporangium sp. BCC 24625. Phytochem Lett 10:149–151CrossRefGoogle Scholar
  21. Lam KS (2006) Discovery of novel metabolites from marine actinomycetes. Curr Opin Microbiol 9:245–251CrossRefPubMedGoogle Scholar
  22. Lane DJ (1991) 16S/23S rRNA sequencing. In: Stackebrandt E, Goodfellow M (ed) Nucleic acid techniques in bacterial systematic. Wiley, Chichester, p 115–175Google Scholar
  23. Lechevalier MP (1975) Actinomycetes of sewage-treatment plants. Environ Prot Technol Ser EPA–600/2–75–031Google Scholar
  24. Lee JH, Kim YG, Kim CJ, Lee JC, Cho MH, Lee J (2012) Indole-3-acetaldehyde from Rhodococcus sp. BFI 332 inhibits Escherichia coli O157:H7 biofilm formation. Appl Microbiol Biotechnol 96:1071–1078CrossRefPubMedGoogle Scholar
  25. Ludwig W, Strunk O, Westram R, Richter L, Meier H, Yadhukumar, Buchner A, Lai T, Steppi S, Jobb G et al. (2004) ARB: a software environment for sequence data. Nucleic Acid Res 32:1363–1371CrossRefPubMedGoogle Scholar
  26. Lyman J, Fleming R (1940) Composition of seawater. J Mar Res 3:134–146Google Scholar
  27. Malvy D, Chappuis F (2011) Sleeping sickness. Clin Microbiol Infect 17:986–995CrossRefPubMedGoogle Scholar
  28. Mincer TJ, Fenical W, Jensen PR (2005) Culture-dependent and culture-independent diversity within the obligate marine actinomycete genus Salinispora. Appl Environ Microbiol 71:7019–7028CrossRefPubMedPubMedCentralGoogle Scholar
  29. Mori T, Aishima T (1992) Specific odor component produced by Mycobacterium lepraemurium on Ogawa yolk medium. Nippon Rai Gakkai Zasshi 61:153–156CrossRefPubMedGoogle Scholar
  30. Nalli Y, Gupta S, Khajuria V, Singh VP, Sajgotra M, Ahmed Z, Thakur NL, Ali A (2016) TNF-α and IL-6 inhibitory effects of cyclic dipeptides isolated from marine bacteria Streptomyces sp. Med Chem Res 26:93–100CrossRefGoogle Scholar
  31. Nawrath T, Mgode GF, Weetjens B, Kaufmann SH, Schulz S (2012) The volatiles of pathogenic and nonpathogenic mycobacteria and related bacteria. Beilstein J Org Chem 8:290–299CrossRefPubMedPubMedCentralGoogle Scholar
  32. Olson JB, Lord CC, McCarthy PG (2000) Improved recoverability of microbial colonies from marine sponge samples. Microb Ecol 40:139–147PubMedGoogle Scholar
  33. Omer ZS, Tombolini R, Broberg A, Gerhardson B (2004) Indole-3-acetic acid production by pink-pigmented facultative methylotrophic bacteria. Plant Growth Regul 43:93–96CrossRefGoogle Scholar
  34. Otsubo K, Morita S, Uchida M, Yamasaki K, Kanbe T, Shimizu T (1991) Synthesis and antiulcer activity of optical isomers of 2-(4-Chlorobenzoylamino)-3[2(1H)-quinolinon-4-yl]propionic acid (Rebamipide). Chem Pharm Bull 39:2906–2909CrossRefPubMedGoogle Scholar
  35. Pan W-B, Chang F-R, Wei L-M, Wu M-J, Wu Y-C (2003) New and efficient method for esterification of carboxylic acids with simple primary and secondary alcohols using cerium (IV) ammonium nitrate (CAN). Tetrahedron Lett 44:331–334CrossRefGoogle Scholar
  36. Pine L, Watson SJ (1959) Evaluation of an isolation and maintenance medium for Actinomyces species and related organisms. J Lab Clin Med 54:107–114PubMedGoogle Scholar
  37. Rather SA, Kumar S, Rah B, Arif M, Ali A, Qazi P (2014) A potent cytotoxic metabolite from terrestrial actinomycete, Streptomyces collinus. Med Chem Res 23:382–387CrossRefGoogle Scholar
  38. Reasoner DJ, Geldreich EE (1985) A new medium for the enumeration and subculture of bacteria from potable water. Appl Environ Microbiol 49:1–7PubMedPubMedCentralGoogle Scholar
  39. Reimer A, Blohm A, Quack T, Grevelding CG, Kozjak-Pavlovic V, Rudel T, Hentschel U, Abdelmohsen UR (2015) Inhibitory activities of the marine streptomycete-derived compound SF2446A2 against Chlamydia trachomatis and Schistosoma mansoni. J Antibiot 68:674–679CrossRefPubMedGoogle Scholar
  40. Sasaki T, Ohtani II, Tanaka J, Higa T (1999) Iheyamines, new cytotoxic bisindole pigments from a colonial ascidian, Polycitorella sp. Tetrahedron Lett 40:303–306CrossRefGoogle Scholar
  41. Sauleau P, Martin MT, Dau ME, Youssef DTA, Bourguet-Kondracki ML (2006) Hyrtiazepine, an azepino-indole-type alkaloid from the Red Sea marine sponge Hyrtios erectus. J Nat Prod 69:1676–1679CrossRefPubMedGoogle Scholar
  42. Shirling EB, Gottlieb D (1966) Methods for characterization of Streptomyces species. Int J Syst Bacteriol 16:313–340CrossRefGoogle Scholar
  43. Steverding D (2010) The development of drugs for treatment of sleeping sickness: a historical review. Parasites Vectors 3:15CrossRefPubMedPubMedCentralGoogle Scholar
  44. Subramani R, Aalbersberg W (2012) Marine actinomycetes: an ongoing source of novel bioactive metabolites. Microbiol Res 167:571–580CrossRefPubMedGoogle Scholar
  45. Sujatha P, Bapi Raju KV, Ramana T (2005) Studies on a new marine streptomycete BT-408 producing polyketide antibiotic SBR-22 effective against methicillin resistant Staphylococcus aureus. Microbiol Res 160:119–126CrossRefPubMedGoogle Scholar
  46. Tabares P, Pimentel-Elardo SM, Schirmeister T, Hunig T, Hentschel U (2011) Anti-protease and immunomodulatory activities of bacteria associated with Caribbean sponges. Mar Biotechnol 13:883–892CrossRefPubMedGoogle Scholar
  47. Taylor MW, Radax R, Steger D, Wagner M (2007) Sponge-associated microorganisms: evolution, ecology, and biotechnological potential. Microbiol Mol Biol Rev 71:295–347CrossRefPubMedPubMedCentralGoogle Scholar
  48. Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG (2015) Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 28:603–661CrossRefPubMedPubMedCentralGoogle Scholar
  49. Tuomi T, Laakso S, Rosenqvist H (1994) Indole-3-acetic acid (Iaa) production by a biofungicide Streptomyces-Griseoviridis strain. Ann Bot Fenn 31:59–63Google Scholar
  50. Wang Q, Garrity GM, Tiedje JM, Cole JR (2007) Naïve Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol 73:5261–5267CrossRefPubMedPubMedCentralGoogle Scholar
  51. Wang H, Jenner AM, Lee C-YJ, Shui G, Tang SY, Whiteman M, Wenk MR, Halliwell B (2007) The identification of antioxidants in dark soy sauce. Free Radic Res 41:479–488CrossRefPubMedGoogle Scholar
  52. Webster NS, Wilson KJ, Blackall LL, Hill RT (2001) Phylogenetic diversity of bacteria associated with the marine sponge Rhopaloeides odorabile. Appl Environ Microbiol 67:434–444CrossRefPubMedPubMedCentralGoogle Scholar
  53. Williams PG, Asolkar RN, Kondratyuk T, Pezzuto JM, Jensen PR, Fenical W (2007) Saliniketals A and B, bicyclic polyketides from the marine actinomycete Salinispora arenicola. J Nat Prod 70:83–88CrossRefPubMedGoogle Scholar
  54. Wu SJ, Fotso S, Li F, Qin S, Laatsch H (2007) Amorphane sesquiterpenes from a marine Streptomyces sp. J Nat Prod 70:304–306CrossRefPubMedGoogle Scholar
  55. Xu X-B, Tang F, Guo X-F, Wang J, Yao X, Sun J, Xun H (2015) Isolation, identification and determination of six nucleosides and two amino acids from bamboo shoots of Gramineae Phyllostachys prominens (WY Xiong). Trop J Pharm Res 14:2239–2246CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Pharmacognosy, Faculty of PharmacyMinia UniversityMiniaEgypt
  2. 2.Department of Botany II, Julius-von-Sachs Institute for Biological SciencesUniversity of WürzburgWürzburgGermany
  3. 3.Department of Pharmacognosy, Faculty of PharmacySuez Canal UniversityIsmailiaEgypt

Personalised recommendations