Microbacterins A and B, New Peptaibols from the Deep Sea Actinomycete <i>Microbacterium sediminis</i> sp. nov. YLB-01(T)

Liu, Dong; Lin, Hong; Proksch, Peter; Tang, Xixiang; Shao, Zhongze; Lin, Wenhan

doi:10.1021/acs.orglett.5b00172

Cited by 46 publications

(46 citation statements)

References 23 publications

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“…Alamethicin, an archetypical peptaibol, was eightfold less potent than 1 against PANC-1 cells (SI Appendix, Table S19). This agrees with widely reported cytotoxic properties described for most known peptaibols (18)(19)(20)(21)(22)(23)(24)(25). To provide an overall better understanding of the antiproliferative and cytotoxic properties of 1, the 10 helix is shown that was generated with Φ-and Ψ-angles of −49°and −29°for poly-Ala dodecamer using the PepMake 1.2 server at pepmake.wishartlab.com/.…”

supporting

confidence: 81%

“…T2, the fungus was grown in several types of broth media. Growth of the fungus in a modified potato dextrose broth (PDB) resulted in the generation of numerous new and known members of the malettinin family of polyketides [malettinins A (27), B (28), and F-H (16)(17)(18)(19)(20), respectively] ( Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

“…The remaining peptides consisted of a series of 11-mer lipopeptaibols (8-13), which were identified as dakwaabakains A-E (8-12) and LP237-F7 (13) (25). residue, β-alanine (BALA), which is otherwise rare among the peptaibols (16,18,30,31) (SI Appendix, Fig. S8A).…”

Section: Resultsmentioning

confidence: 99%

“…The peptaibols have been intensively studied because of their abilities to form pores in the outer membranes of cells; these pore-forming capabilities result in most compounds in this class exhibiting nonspecific cytotoxic properties toward bacterial, fungal, and mammalian cells (15,17). The effects of peptaibols on mammalian cells tend to be relatively modest, causing the loss of cell viability at concentrations in the mid-to-high micromolar range (18)(19)(20)(21)(22)(23)(24)(25). With many hundreds of peptaibols reported, finding new peptaibol analogs that possess an alternative mode of biological activity would be an impracticable prospect if one relied solely on either chemically driven or genome-based approaches to identify candidate molecules.…”

Section: Significancementioning

confidence: 99%

“…The mechanism of cell cytotoxicity induced by the peptaibols has been extensively studied and it has been consistently demonstrated that their abilities to induce cell death are related to their pore-forming capabilities (18)(19)(20)(21)(22)(23)(24)(25). Considering the increased potencies and unique structural features of the gichigamins, we first investigated whether these peptaibols incorporate into membranes to form pores.…”

mentioning

confidence: 99%

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Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Risinger²,

Mitchell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mass-spectrometry-based metabolomics and molecular phylogeny data were used to identify a metabolically prolific strain of Tolypocladium that was obtained from a deep-water Great Lakes sediment sample. An investigation of the isolate's secondary metabolome resulted in the purification of a 22-mer peptaibol, gichigamin A (1). This peptidic natural product exhibited an amino acid sequence including several β-alanines that occurred in a repeating ααβ motif, causing the compound to adopt a unique right-handed 3 11 helical structure. The unusual secondary structure of 1 was confirmed by spectroscopic approaches including solution NMR, electronic circular dichroism (ECD), and single-crystal X-ray diffraction analyses. Artificial and cell-based membrane permeability assays provided evidence that the unusual combination of structural features in gichigamins conferred on them an ability to penetrate the outer membranes of mammalian cells. Compound 1 exhibited potent in vitro cytotoxicity (GI 50 0.55 ± 0.04 μM) and in vivo antitumor effects in a MIA PaCa-2 xenograft mouse model. While the primary mechanism of cytotoxicity for 1 was consistent with ion leakage, we found that it was also able to directly depolarize mitochondria. Semisynthetic modification of 1 provided several analogs, including a C-terminus-linked coumarin derivative (22) that exhibited appreciably increased potency (GI 50 5.4 ± 0.1 nM), but lacked ion leakage capabilities associated with a majority of naturally occurring peptaibols such as alamethicin. Compound 22 was found to enter intact cells and induced cell death in a process that was preceded by mitochondrial depolarization.peptaibol | fungi | natural products | gichigamin | mitochondria N atural product chemical research has evolved in many extraordinary ways over the last decade largely due to the integration of powerful and accessible analytical chemistry (1, 2) and molecular biology (3, 4) tools. Some of these techniques have been applied toward the creation of natural product big-data sets in which genomic, metagenomic, metabolomic, and proteomic approaches are combined to obtain new insights into nature's remarkable chemical bounty (4-8). The predictive capabilities of these methods have helped guide efforts in several fertile areas of natural products research including the DNA cross-linking enediynes (9), bioactive cyanobacterial metabolites (10, 11), cytotoxic pentangular polyphenols (12), and thiopeptide antibiotics (13).The integration of analytical and molecular approaches is an effective way to find new natural product analogs that exhibit enhanced biological activities and improved pharmacological attributes (e.g., greater potency, better solubility, enhanced therapeutic index, etc.), but it also has the potential to uncover compounds with activities that are markedly dissimilar to other members of the queried chemical class. Nature is well known for its chemical repurposing capabilities, which allow populations of organisms to evolve new biological functions from existing molecular sc...

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supporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

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Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Risinger²,

Mitchell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Identification and Biological Activities of Long‐Chain Peptaibols Produced by a Marine‐Derived Strain of Trichoderma longibrachiatum

Mohamed-Benkada

Pouchus

Vérité

et al. 2016

Chemistry & Biodiversity

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Six long-chain peptaibols, 1 - 6, were identified from agar cultures of a marine-derived Trichoderma longibrachiatum Rifai strain (MMS151) isolated from blue mussels. The structure elucidation was carried out using electrospray ionization ion trap mass spectrometry (ESI-IT-MS) and GC/EI-MS. The long-chain peptaibols exhibited the general building scheme Ac-Aib-Ala-Aib-Ala-Aib-XXX-Gln-Aib-Vxx-Aib-Gly-XXX-Aib-Pro-Vxx-Aib-XXX-Gln-Gln-Pheol and were similar or identical to recurrent 20-residue peptaibols produced by Trichoderma spp. Three new sequences were identified and were called longibrachins A-0, A-II-a, and A-IV-b. The isolated peptaibols were assayed for cytotoxic, antibacterial, and antifungal activities, and acute toxicity on Dipteran larvae.

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New Resorcinol Derivatives from a Sponge‐Derived Fungus Hansfordia sinuosae

Liu

et al. 2017

Chemistry & Biodiversity

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Ten new resorcinol derivatives named hansfordiols A - J (1 - 10) were isolated from the fermentation broth of the sponge-derived fungus Hansfordia sinuosae. High resolution electron ionization mass spectrometry, FT-IR spectroscopy, and NMR techniques were used to elucidate the structures of these compounds, and the absolute configurations were established by the modified Mosher's method and their specific optical rotation. The structures of compounds 8 - 10 were featured with various chlorination at aromatic rings. Their antioxidant activities on ABTS, cytotoxicity on the HCT-8, Bel-7402, BGC-823, A549, and A2780 cell lines, and antibacterial activities were evaluated.

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Microbacterins A and B, New Peptaibols from the Deep Sea Actinomycete Microbacterium sediminis sp. nov. YLB-01(T)

Cited by 46 publications

References 23 publications

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Identification and Biological Activities of Long‐Chain Peptaibols Produced by a Marine‐Derived Strain of Trichoderma longibrachiatum

New Resorcinol Derivatives from a Sponge‐Derived Fungus Hansfordia sinuosae

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