The bacterial thiopeptide thiostrepton. An update of its mode of action, pharmacological properties and applications

Bailly, Christian

doi:10.1016/j.ejphar.2021.174661

Cited by 24 publications

(15 citation statements)

References 192 publications

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“…Thiostrepton (TST) is a protein translation inhibitor that is essentially active against Gram-positive bacteria and some Gram-negative bacteria [ 9 ]. In previous research, TST has been reported to inhibit FOXM1 and the malignant behaviour of a variety of tumours, including colorectal cancer, breast cancer, lung cancer, acute lymphoblastic leukaemia, ovarian cancer, and even pancreatic cancer [ 10 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling

et al. 2022

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Ferroptosis is a new form of regulated cell death that is mediated by intracellular iron and ester oxygenase, and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into nontoxic lipid alcohols. Although thiostrepton (TST) has been reported to exert antitumor effects, its role in pancreatic cancer and the underlying mechanisms remain unclear. In this study, we found that TST reduced the viability and clonogenesis of pancreatic cancer cell lines, along with intracellular iron overload, increasing reactive oxygen species (ROS) accumulation, malondialdehyde (MDA) overexpression, and glutathione peroxidase (GSH-PX) depletion. Mechanistically, chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays were used to confirm that signal transducer and activator of transcription 3 (STAT3) binds to the GPX4 promoter region and promotes its transcription, whereas TST blocked GPX4 expression by regulating STAT3. Finally, in vivo experiments revealed that TST inhibited the growth of subcutaneously transplanted tumours and had considerable biosafety. In conclusion, our study identified the mechanism by which TST-induced ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling.

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Section: Introductionmentioning

confidence: 99%

Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling

et al. 2022

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“…Several attempts at structural characterization using NMR spectroscopy have been unsuccessful due to aggregation and insolubility of the compound. 218 Several other peptides with sequence homology to SapB have been identified including AmfS (36), produced in Streptomyces griseus (Figure 14). 223,224 AmfS is also important for aerial hyphae formation and sporulation.…”

Section: Class III Lanthipeptidesmentioning

confidence: 99%

“…In turn, the wide variety of natural targets and activities suggests that this class of compounds offers much promise for discovery and engineering of new activities. This review will provide a comprehensive discussion of the MOA of bacterial RiPPs for which such information is available, to complement earlier reviews that focused on specific compound classes or a subset of RiPPs. − The review covers studies reported up to and including 2021.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides

et al. 2022

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a natural product class that has undergone significant expansion due to the rapid growth in genome sequencing data and recognition that they are made by biosynthetic pathways that share many characteristic features. Their mode of actions cover a wide range of biological processes and include binding to membranes, receptors, enzymes, lipids, RNA, and metals as well as use as cofactors and signaling molecules. This review covers the currently known modes of action (MOA) of RiPPs. In turn, the mechanisms by which these molecules interact with their natural targets provide a rich set of molecular paradigms that can be used for the design or evolution of new or improved activities given the relative ease of engineering RiPPs. In this review, coverage is limited to RiPPs originating from bacteria.

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“… a Examples of RiPPs with biological activities relevant to human society. Nisin is used commercially in the food industry to combat food-borne pathogens 38 , duramycin is used in diagnostics 76 , thiostrepton is used in veterinary medicine 77 , and microcin J25 is a bacterial RNA polymerase inhibitor 6 . Structural motifs formed during PTMs are shown in red.…”

Section: Introductionmentioning

confidence: 99%

A scalable platform to discover antimicrobials of ribosomal origin

et al. 2022

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a promising source of new antimicrobials in the face of rising antibiotic resistance. Here, we report a scalable platform that combines high-throughput bioinformatics with automated biosynthetic gene cluster refactoring for rapid evaluation of uncharacterized gene clusters. As a proof of concept, 96 RiPP gene clusters that originate from diverse bacterial phyla involving 383 biosynthetic genes are refactored in a high-throughput manner using a biological foundry with a success rate of 86%. Heterologous expression of all successfully refactored gene clusters in Escherichia coli enables the discovery of 30 compounds covering six RiPP classes: lanthipeptides, lasso peptides, graspetides, glycocins, linear azol(in)e-containing peptides, and thioamitides. A subset of the discovered lanthipeptides exhibit antibiotic activity, with one class II lanthipeptide showing low µM activity against Klebsiella pneumoniae, an ESKAPE pathogen. Overall, this work provides a robust platform for rapidly discovering RiPPs.

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The bacterial thiopeptide thiostrepton. An update of its mode of action, pharmacological properties and applications

Cited by 24 publications

References 192 publications

Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling

Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling

Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides

A scalable platform to discover antimicrobials of ribosomal origin

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