A Fluorescent Probe for the 70 S‐Ribosomal GTPase‐Associated Center

Schoof, Sebastian; Baumann, Sascha; Ellinger, Bernhard; Arndt, Hans‐Dieter

doi:10.1002/cbic.200800642

Cited by 47 publications

(65 citation statements)

References 42 publications

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“…The thiostrepton-based compounds were synthesized as described previously (46). The synthesis of the fluorescent thiostrepton probe was described previously (45).…”

Section: Methodsmentioning

confidence: 99%

Thiostrepton and Derivatives Exhibit Antimalarial and Gametocytocidal Activity by Dually Targeting Parasite Proteasome and Apicoplast

Aminake

Schoof

Sologub

et al. 2011

Antimicrob Agents Chemother

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116

111

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Ribosome-targeting antibiotics exert their antimalarial activity on the apicoplast of the malaria parasite, an organelle of prokaryote origin having essential metabolic functions. These antibiotics typically cause a delayeddeath phenotype, which manifests in parasite killing during the second replication cycle following administration. As an exception, treatment with the antibiotic thiostrepton results in an immediate killing. We recently demonstrated that thiostrepton and its derivatives interfere with the eukaryotic proteasome, a multimeric protease complex that is important for the degradation of ubiquitinated proteins. Here, we report that the thiostrepton-based compounds are active against chloroquine-sensitive and -resistant Plasmodium falciparum, where they rapidly eliminate parasites before DNA replication. The minor parasite fraction that escapes the fast killing of the first replication cycle is arrested in the schizont stage of the following cycle, displaying a delayed-death phenotype. Thiostrepton further exhibits gametocytocidal activity by eliminating gametocytes, the sexual precursor cells that are crucial for parasite transmission to the mosquito. Compound treatment results in an accumulation of ubiquitinated proteins in the blood stages, indicating an effect on the parasite proteasome. In accordance with these findings, expression profiling revealed that the proteasome is present in the nucleus and cytoplasm of trophozoites, schizonts, and gametocytes. In conclusion, thiostrepton derivatives represent promising candidates for malaria therapy by dually acting on two independent targets, the parasite proteasome and the apicoplast, with the capacity to eliminate both intraerythrocytic asexual and transmission stages of the parasite.

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“…The thiostrepton-based compounds were synthesized as described previously (46). The synthesis of the fluorescent thiostrepton probe was described previously (45).…”

Section: Methodsmentioning

confidence: 99%

Thiostrepton and Derivatives Exhibit Antimalarial and Gametocytocidal Activity by Dually Targeting Parasite Proteasome and Apicoplast

Aminake

Schoof

Sologub

et al. 2011

Antimicrob Agents Chemother

Self Cite

116

111

View full text Add to dashboard Cite

show abstract

“…Furthermore, thiostrepton inhibits the proteasome in eukaryotic cells (42,43) exerting antimalarial (44,45) and anticancer (42)(43)(44)(45)(46)(47) activities. Despite their unique mechanism of action and their high potency against pathogens such as methicillin-resistant Staphylococcus aureus and Enterococcus faecium or penicillin-resistant Streptococcus pneumonia (48), the clinical application of thiopeptides is impeded by their considerable size and low water solubility (35,(48)(49)(50)(51). However, recent progress in thiopeptide chemical synthesis (43,52), biosynthesis (53,54), and activity screens (55) may enable the development of new thiopeptide derivatives with improved pharmaceutical properties.…”

Section: Significancementioning

confidence: 99%

Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system

Habazettl

Allan

Jensen

et al. 2014

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

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Significance Multidrug recognition is an important phenomenon that is not well understood. TipA, a bacterial transcriptional regulator, constitutes a minimal multidrug resistance system against numerous thiopeptide antibiotics. We show that motions in the millisecond to microsecond time range form the basis of the TipA multidrug recognition mechanism. This may be common to many multidrug recognition systems. The discovery that the structural antibiotic motifs essential for binding to TipA and to the ribosome are identical makes the multidrug recognition mechanism of TipA a useful model for ribosomal thiopeptide binding and current antibiotic drug development.

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“…This reaction is highly specific for the alkyne group of ProcK, and did not produce side products from modification of other chemical functionalities in thiocillin. This is advantageous compared with previous methods using thiolMichael addition to dehydroamino acids (35), as these residues occur frequently in thiopeptides (36). A similar approach was used to create an activity probe containing a biotin-diazirine linker that allows cross-linking of thiocillin to its cellular target.…”

Section: Discussionmentioning

confidence: 99%

Recombinant thiopeptides containing noncanonical amino acids

Luo

Zambaldo

Liu

et al. 2016

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

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Thiopeptides are a subclass of ribosomally synthesized and posttranslationally modified peptides (RiPPs) with complex molecular architectures and an array of biological activities, including potent antimicrobial activity. Here we report the generation of thiopeptides containing noncanonical amino acids (ncAAs) by introducing orthogonal amber suppressor aminoacyl-tRNA synthetase/tRNA pairs into a thiocillin producer strain of Bacillus cereus. We demonstrate that thiopeptide variants containing ncAAs with bioorthogonal chemical reactivity can be further postbiosynthetically modified with biophysical probes, including fluorophores and photo-cross-linkers. This work allows the site-specific incorporation of ncAAs into thiopeptides to increase their structural diversity and probe their biological activity; similar approaches can likely be applied to other classes of RiPPs.noncanonical amino acid | biosynthesis | natural products | thiopeptides | antibiotic

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A Fluorescent Probe for the 70 S‐Ribosomal GTPase‐Associated Center

Cited by 47 publications

References 42 publications

Thiostrepton and Derivatives Exhibit Antimalarial and Gametocytocidal Activity by Dually Targeting Parasite Proteasome and Apicoplast

Thiostrepton and Derivatives Exhibit Antimalarial and Gametocytocidal Activity by Dually Targeting Parasite Proteasome and Apicoplast

Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system

Recombinant thiopeptides containing noncanonical amino acids

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