Litoralimycins A and B, New Cytotoxic Thiopeptides from Streptomonospora sp. M2

Streptomonospora sp. M2 has been isolated from a soil sample collected at the Wadden Sea beach in our ongoing program aimed at the isolation of rare Actinobacteria, ultimately targeting the discovery of new antibiotics. Because crude extracts derived from cultures of this strain showed inhibitory activity against the indicator organism Bacillus subtilis, it was selected for further analysis. HPLC–MS analysis of its culture broth revealed the presence of lipophilic metabolites. The two major metabolites of those were isolated by preparative reversed-phase HPLC and preparative TLC. Their planar structures were elucidated using high-resolution electrospray ionization mass spectrometry (HRESIMS), 1D and 2D NMR data as new thiopeptide antibiotics and named litoralimycin A (1) and B (2). Although rotating frame nuclear Overhauser effect spectroscopy (ROESY) data established a Z configuration of the Δ21,26 double bond, the stereochemistry of C-5 and C-15 were assigned as S by Marfey’s method after ozonolysis. The biological activity spectrum of 1 and 2 is highly uncommon for thiopeptide antibiotics, since they showed only insignificant antibacterial activity, but 1 showed strong cytotoxic effects.

[1]  Jiangtao Gao,et al.  Natural thiopeptides as a privileged scaffold for drug discovery and therapeutic development , 2019, Medicinal Chemistry Research.

[2]  M. Stadler,et al.  Antiviral Meroterpenoid Rhodatin and Sesquiterpenoids Rhodocoranes A-E from the Wrinkled Peach Mushroom, Rhodotus palmatus. , 2019, Organic letters.

[3]  M. Stadler,et al.  Hyfraxins A and B, cytotoxic ergostane-type steroid and lanostane triterpenoid glycosides from the invasive ash dieback ascomycete Hymenoscyphus fraxineus , 2018, Steroids.

[4]  O. Genilloud.  Actinomycetes: still a source of novel antibiotics. , 2017, Natural product reports.

[5]  Wiebke Landwehr,et al.  Actinobacteria and Myxobacteria-Two of the Most Important Bacterial Resources for Novel Antibiotics. , 2016, Current topics in microbiology and immunology.

[6]  M. Stadler,et al.  How to Overcome the Antibiotic Crisis , 2016, Current Topics in Microbiology and Immunology.

[7]  F. Albericio,et al.  Thiopeptide Antibiotics: Retrospective and Recent Advances , 2014, Marine drugs.

[8]  R. Müller,et al.  Concerted action of P450 plus helper protein to form the amino-hydroxy-piperidone moiety of the potent protease inhibitor crocapeptin. , 2013, Journal of the American Chemical Society.

[9]  R. Subramani,et al.  Culturable rare Actinomycetes: diversity, isolation and marine natural product discovery , 2013, Applied Microbiology and Biotechnology.

[10]  Steven J. Malcolmson,et al.  The posttranslational modification cascade to the thiopeptide berninamycin generates linear forms and altered macrocyclic scaffolds , 2013, Proceedings of the National Academy of Sciences.

[11]  K. Tiwari,et al.  Rare actinomycetes: a potential storehouse for novel antibiotics , 2012, Critical reviews in biotechnology.

[12]  S. Balasubramanian,et al.  The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. , 2011, Nature chemistry.

[13]  H. Kawai,et al.  PHYSICO-CHEMICAL PROPERTIES AND STRUCTURE DETERMINATION , 2006 .

[14]  A. Murchie,et al.  Structural basis for contrasting activities of ribosome binding thiazole antibiotics. , 2003, Chemistry & biology.

[15]  J. M. Fernández-Abalos,et al.  Radamycin, a novel thiopeptide produced by streptomyces sp. RSP9. I. Taxonomy, fermentation, isolation and biological activities. , 2002, The Journal of antibiotics.

[16]  L. Cañedo,et al.  Radamycin, a novel thiopeptide produced by streptomyces sp. RSP9. II. Physico-chemical properties and structure determination. , 2002, The Journal of antibiotics.

[17]  H. Seto,et al.  Absolute stereochemistry and solution conformation of promothiocins , 2001 .

[18]  J. Vohradský,et al.  Broad Spectrum Thiopeptide Recognition Specificity of theStreptomyces lividans TipAL Protein and Its Role in Regulating Gene Expression* , 1999, The Journal of Biological Chemistry.

[19]  M. Ottesen,et al.  Determination ofd-amino acids. I. Hydrolysis of DNP-l-amino acid methyl esters with carboxypeptidase-Y , 1984 .