TY  - JOUR
A1  - Pimentel-Elardo, Sheila M.
A1  - Buback, Verena
A1  - Gulder, Tobias A. M.
A1  - Bugni, Tim S.
A1  - Reppart, Jason
A1  - Bringmann, Gerhard
A1  - Ireland, Chris M.
A1  - Schirmeister, Tanja
A1  - Hentschel, Ute
T1  - New Tetromycin Derivatives with Anti-Trypanosomal and Protease Inhibitory Activities
JF  - Marine drugs
N2  - Four new tetromycin derivatives, tetromycins 1-4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001(T) cultivated from the Mediterranean sponge Axinella polypoides. Structures were assigned using extensive 1D and 2D NMR spectroscopy as well as HRESIMS analysis. The compounds were tested for antiparasitic activities against Leishmania major and Trypanosoma brucei, and for protease inhibition against several cysteine proteases such as falcipain, rhodesain, cathepsin L, cathepsin B, and viral proteases SARS-CoV M(pro), and PL(pro). The compounds showed antiparasitic activities against T. brucei and time-dependent inhibition of cathepsin L-like proteases with K(i) values in the low micromolar range.
KW  - cysteine protease
KW  - drugs
KW  - streptomyces
KW  - discovery
KW  - anti-trypanosomal
KW  - protease inhibition
KW  - Streptomyces axinellae
KW  - marine sponge
KW  - tetromycin
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141171
VL  - 9
IS  - 10
ER  - 
TY  - JOUR
A1  - Cecil, Alexander
A1  - Rikanovic, Carina
A1  - Ohlsen, Knut
A1  - Liang, Chunguang
A1  - Bernhardt, Jorg
A1  - Oelschlaeger, Tobias A.
A1  - Gulder, Tanja
A1  - Bringmann, Gerd
A1  - Holzgrabe, Ulrike
A1  - Unger, Matthias
A1  - Dandekar, Thomas
T1  - Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells
N2  - Background: Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine. Results: Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity. Conclusions: The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics.
KW  - Staphylococcus aureus
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68802
ER  - 
TY  - JOUR
A1  - Pimentel-Elardo, Sheila M.
A1  - Buback, Verena
A1  - Gulder, Tobias A. M.
A1  - Bugni, Tim S.
A1  - Reppart, Jason
A1  - Bringmann, Gerhard
A1  - Ireland, Chris M.
A1  - Schirmeister, Tanja
A1  - Hentschel, Ute
T1  - New Tetromycin Derivatives with Anti-Trypanosomal and Protease Inhibitory Activities
N2  - Four new tetromycin derivatives, tetromycins 1–4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001T cultivated from the Mediterranean sponge Axinella polypoides. Structures were assigned using extensive 1D and 2D NMR spectroscopy as well as HRESIMS analysis. The compounds were tested for antiparasitic activities against Leishmania major and Trypanosoma brucei, and for protease inhibition against several cysteine proteases such as falcipain, rhodesain, cathepsin L, cathepsin B, and viral proteases SARS-CoV Mpro, and PLpro. The compounds showed antiparasitic activities against T. brucei and time-dependent inhibition of cathepsin L-like proteases with Ki values in the low micromolar range.
KW  - Biologie
KW  - tetromycin
KW  - anti-trypanosomal
KW  - protease inhibition
KW  - Streptomyces axinellae
KW  - marine sponge
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75465
ER  -