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Ahmed Lebrihi - One of the best experts on this subject based on the ideXlab platform.
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Identification of Two Putative Acyltransferase Genes Potentially Implicated in Dithiolopyrrolone Biosyntheses in Saccharothrix algeriensis NRRL B-24137
Applied Biochemistry and Biotechnology, 2014Co-Authors: Safwan Saker, Ahmed Lebrihi, Florence MathieuAbstract:The dithiolopyrrolone class of antibiotics has been known to display bacteriostatic activity against both Gram-positive and Gram-negative bacteria and exert other biological activities. Acyltransferase activities are proposed to be responsible for the structural diversity of dithiolopyrrolones produced by Saccharothrix algeriensis NRRL B-24137. Moreover, two activities, pyrrothine N-acetyltransferase and pyrrothine N-benzoyltransferase, are reported to catalyze the formation, respectively, to Thiolutin and benzoyl-pyrrothine (BEP) in this bacterium. In this study, two genes encoding two putative acyltransferases were identified in S. algeriensis. The first one, actA, was identified by bioinformatic analysis and by analogy to an acetyltransferase, hlmA, identified in holomycin biosynthetic gene cluster in Streptomyces clavuligerus. The second was identified by purification of both enzymes from the bacterial biomass which provided a semipurified extract. The microsequencing of tryptic peptides from the final protein preparation yielded sequences of eight different fragments, two of them encoded by one gene, actB, in S. algeriensis genome bank. The alignment of actB against the GenBank database revealed significant homology to acyltransferase family. Differential expression of these genes, actA and actB, was then investigated in three different media: (i) semisynthetic medium (SSM), which promotes the production of Thiolutin; (ii) SSM supplemented by 1.25 mM benzoic acid (SSM + BA), which promotes the production of both Thiolutin and BEP; and (iii) tryptic soy broth (TSB) in which no dithiolopyrrolone derivatives were detected.
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Enzymatic Synthesis of Dithiolopyrrolone Antibiotics Using Cell-Free Extract of Saccharothrix algeriensis NRRL B-24137 and Biochemical Characterization of Two Pyrrothine N-Acyltransferases in This Extract.
Journal of microbiology and biotechnology, 2014Co-Authors: Safwan Saker, Ahmed Lebrihi, Ziade Almousa Almaksour, Anne-claire Chorin, Florence MathieuAbstract:Saccharothrix algeriensis NRRL B-24137 produces naturally different dithiolopyrrolone derivatives. The enzymatic activity of pyrrothine N-acyltransferase was determined to be responsible for the transfer of an acyl group from acyl-CoA to pyrrothine core. This activity was also reported to be responsible for the diversity of the dithiolopyrrolone derivatives. Based on this fact, nine dithiolopyrrolone derivatives were produced in vitro via the crude extract of Sa. algeriensis. Three of them have never been obtained before by natural fermentation: acetoacetyl-pyrrothine, hydroxybutyryl-pyrrothine, and dimethyl Thiolutin (holomycin). Two acyltransferase activities, acetyltransferase and benzoyltransferase catalyzing the incorporation of linear and cyclic acyl groups to the pyrrothine core, respectively, were biochemically characterized in this crude extract. The first one is responsible for formation of acetyl-pyrrothine and the second for benzoyl-pyrrothine. Both enzymes were sensitive to temperature changes: For example, the loss of acetyltransferase and benzoyltransferase activity was 53% and 80% respectively after pre-incubation of crude extract for 60 min at 20°C. The two enzymes were more active in neutral and basal media (pH 7-10) than in the acidic one (pH 3-6). The optimum temperature and pH of acetyltransferase were 40°C and 7, with a Km value of 7.9 μM and a Vmax of 0.63 μM/min when acetyl-CoA was used as limited substrate. Benzoyltransferase had a temperature and a pH optimum at 55°C and 9, a Km value of 14.7 μM, and a Vmax of 0.67 μM/min when benzoyl- CoA was used as limited substrate.
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A stoichiometric reaction scheme for Saccharothrix algeriensis growth and Thiolutin production.
Process Biochemistry, 2010Co-Authors: Caroline Strub, Cédric Brandam, Xuân-mi Meyer, Ahmed LebrihiAbstract:A new bacterial species, Saccharothrix algeriensis NRRL B-24137, was isolated in 1992 in the Sahara desert. This filamentous bacterium is able to produce dithiolopyrrolones, molecules presenting antibacterial, antifungal, and anticancer properties. In this study, a “reaction engineering” approach was adopted to gain more knowledge on the growth of Sa. algeriensis and its dithiolopyrrolone production on a semi-synthetic liquid medium. The objective is to establish a reaction scheme of the bacterium metabolism from extracellular experimental information, relatively easy to obtain. The approach enabled us to show that Sa. algeriensis could grow using several substrates that were sequentially consumed and that substrate limitation may induce a secondary metabolism in antibiotic production. From these qualitative data, a general reaction scheme was extracted consisting of four reactions: growth via amino acids, glucose consumption for maintenance, growth using glucose, and Thiolutin production. The stoichiometric coefficients and the reaction extends were identified using a factorial analysis based on the bilinear structure of the component mass balances in a batch reactor. The analysis of the reaction stoichiometry enabled us to draw some conclusions concerning the substrate consumption pathway.
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effect of amino acids containing sulfur on dithiolopyrrolone antibiotic productions by saccharothrix algeriensis nrrl b 24137
Journal of Applied Microbiology, 2006Co-Authors: Noureddine Bouras, Florence Mathieu, Nasserdine Sabaou, Ahmed LebrihiAbstract:Aims: To study the effect of sulfur-containing amino acids (L-cysteine, L-cystine, L-methionine and DL-ethionine) on the production of dithiolopyrrolone antibiotics by Saccharothrix algeriensis NRRL B-24137. Methods and Results: The production levels of dithiolopyrrolones were investigated by using high performance liquid chromatography in a chemically semi-synthetic medium. The production of the studied antibiotics depends upon the nature, concentration and the time of addition of these sources in the culture medium. Both cysteine and cystine favoured the specific productions of dithiolopyrrolones; iso-butyryl-pyrrothine (ISP) by cysteine, however butanoyl-pyrrothine, senecioyl-pyrrothine and tigloyl-pyrrothine by cystine, when added initially to the culture medium. The maximum specific productions of dithiolopyrrolones were observed in the presence of 5 mmol l−1 cystine for Thiolutin, 5 mmol l−1 cysteine for ISP, and 10 mmol l−1 cystine for others studied dithiolopyrrolones as shown in Fig. 3. The production of these antibiotics was decreased when the concentrations of cysteine and cystine were in excess. All dithiolopyrrolone specific productions were strongly inhibited by addition of methionine and ethionine, without inhibition of mycelial growth. Figure 3. Effect of cysteine () and cystine () addition at different concentrations on specific production of Thiolutin (a), senecioyl-pyrrothine (b), tigloyl-pyrrothine (c), iso-butyryl-pyrrothine (d) and butanoyl-pyrrothine (e). Specific dithiolopyrrolone productions are given as mg per g of biomass at the time of maximal productions during 96 h of fermentation. Download figure to PowerPoint Conclusions: Among all studied amino acids, cystine and cysteine can be used as supplements for improvement the production of dithiolopyrrolone antibiotics by S. algeriensis NRRL B-24137. Significance and Impact of the Study: Dithiolopyrrolone antibiotics have many important applications for employing them as medicaments, particularly in the treatment of human and animal cancers. In the present work, the influence of containing-sulfur amino acids on dithiolopyrrolone antibiotic productions was studied. The obtained results can be employed for the optimization of the culture medium for the dithiolopyrrolone productions in higher quantities.
Barry L. Karger - One of the best experts on this subject based on the ideXlab platform.
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Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton
Cell Stress and Chaperones, 2010Co-Authors: Shiaw-lin Wu, Lyndsay Field, Bixi Zeng, Russell W Bandle, John M Sipes, Ramani Ramchandran, Lisa A. Ridnour, David A. Wink, Jeffrey Scott Isenberg, Barry L. KargerAbstract:Thiolutin is a dithiole synthesized by Streptomyces sp. that inhibits endothelial cell adhesion and tumor growth. We show here that Thiolutin potently inhibits developmental angiogenesis in zebrafish and vascular outgrowth from tissue explants in 3D cultures. Thiolutin is a potent and selective inhibitor of endothelial cell adhesion accompanied by rapid induction of HSPB1 (Hsp27) phosphorylation. The inhibitory effects of Thiolutin on endothelial cell adhesion are transient, potentially due to a compensatory increase in Hsp27 protein levels. Accordingly, heat shock induction of Hsp27 limits the anti-adhesive activity of Thiolutin. Thiolutin treatment results in loss of actin stress fibers, increased cortical actin as cells retract, and decreased cellular F-actin. Mass spectrometric analysis of Hsp27 binding partners following immunoaffinity purification identified several regulatory components of the actin cytoskeleton that associate with Hsp27 in a Thiolutin-sensitive manner including several components of the Arp2/3 complex. Among these, ArpC1a is a direct binding partner of Hsp27. Thiolutin treatment induces peripheral localization of phosphorylated Hsp27 and Arp2/3. Hsp27 also associates with the intermediate filament components vimentin and nestin. Thiolutin treatment specifically ablates Hsp27 interaction with nestin and collapses nestin filaments. These results provide new mechanistic insights into regulation of cell adhesion and cytoskeletal dynamics by Hsp27.
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comprehensive characterization of heat shock protein 27 phosphorylation in human endothelial cells stimulated by the microbial dithiole Thiolutin
Journal of Proteome Research, 2008Co-Authors: Shiaw-lin Wu, Russell W Bandle, Lisa A. Ridnour, David A. Wink, Jeffrey S Isenberg, David D Roberts, Barry L. KargerAbstract:Thiolutin is a sulfur-based microbial compound with known activity as an angiogenesis inhibitor. Relative to previously studied angiogenesis inhibitors, Thiolutin is a remarkably potent inducer of heat shock protein 27 (Hsp27) phosphorylation. This phosphorylation requires p38 kinase but is independent of increased p38 phosphorylation. To elucidate how Thiolutin regulates Hsp27 phosphorylation and ultimately angiogenesis, Hsp27 was immunoprecipitated using nonphosphorylated and phospho-Ser78 specific antibodies from lysates of Thiolutin treated and untreated human umbilical vein endothelial cells and analyzed by LC–MS. Separate LC–MS analyses of Lys-C, Lys-C plus trypsin, and Lys-C plus Glu-C digests provided 100% sequence coverage, including the identification of a very large 13 kDa Lys-C fragment using a special sample handling procedure (4 M guanidine HCl) prior to the LC–MS analysis to improve the large peptide recovery. The analysis revealed a novel post-translational modification of Hsp27 involving truncation of the N-terminal Met and acetylation of the penultimate Thr. Analysis of a Glu-C fragment containing two phosphorylation sites, Ser78 and Ser82, and a tryptic fragment containing the other phosphorylation site, Ser15, enabled quantitative stoichiometry of Hsp27 phosphorylation by LC–MS. The strategy revealed details of Hsp27 phosphorylation, including significant di-phosphorylation at both Ser78 and Ser82, that would be difficult to obtain by traditional approaches because oligomerization of the hydrophobic N-terminal region of the molecule prevents efficient enzymatic cleavage. The combination of Western blotting, immunoprecipation, and LC–MS provides a quantitative analysis of Thiolutin-stimulated Hsp27 phosphorylation and further defines the role of Hsp27 in the antiangiogenic activities of Thiolutin and related dithiolethiones.
Florence Mathieu - One of the best experts on this subject based on the ideXlab platform.
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Identification of Two Putative Acyltransferase Genes Potentially Implicated in Dithiolopyrrolone Biosyntheses in Saccharothrix algeriensis NRRL B-24137
Applied Biochemistry and Biotechnology, 2014Co-Authors: Safwan Saker, Ahmed Lebrihi, Florence MathieuAbstract:The dithiolopyrrolone class of antibiotics has been known to display bacteriostatic activity against both Gram-positive and Gram-negative bacteria and exert other biological activities. Acyltransferase activities are proposed to be responsible for the structural diversity of dithiolopyrrolones produced by Saccharothrix algeriensis NRRL B-24137. Moreover, two activities, pyrrothine N-acetyltransferase and pyrrothine N-benzoyltransferase, are reported to catalyze the formation, respectively, to Thiolutin and benzoyl-pyrrothine (BEP) in this bacterium. In this study, two genes encoding two putative acyltransferases were identified in S. algeriensis. The first one, actA, was identified by bioinformatic analysis and by analogy to an acetyltransferase, hlmA, identified in holomycin biosynthetic gene cluster in Streptomyces clavuligerus. The second was identified by purification of both enzymes from the bacterial biomass which provided a semipurified extract. The microsequencing of tryptic peptides from the final protein preparation yielded sequences of eight different fragments, two of them encoded by one gene, actB, in S. algeriensis genome bank. The alignment of actB against the GenBank database revealed significant homology to acyltransferase family. Differential expression of these genes, actA and actB, was then investigated in three different media: (i) semisynthetic medium (SSM), which promotes the production of Thiolutin; (ii) SSM supplemented by 1.25 mM benzoic acid (SSM + BA), which promotes the production of both Thiolutin and BEP; and (iii) tryptic soy broth (TSB) in which no dithiolopyrrolone derivatives were detected.
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Enzymatic Synthesis of Dithiolopyrrolone Antibiotics Using Cell-Free Extract of Saccharothrix algeriensis NRRL B-24137 and Biochemical Characterization of Two Pyrrothine N-Acyltransferases in This Extract.
Journal of microbiology and biotechnology, 2014Co-Authors: Safwan Saker, Ahmed Lebrihi, Ziade Almousa Almaksour, Anne-claire Chorin, Florence MathieuAbstract:Saccharothrix algeriensis NRRL B-24137 produces naturally different dithiolopyrrolone derivatives. The enzymatic activity of pyrrothine N-acyltransferase was determined to be responsible for the transfer of an acyl group from acyl-CoA to pyrrothine core. This activity was also reported to be responsible for the diversity of the dithiolopyrrolone derivatives. Based on this fact, nine dithiolopyrrolone derivatives were produced in vitro via the crude extract of Sa. algeriensis. Three of them have never been obtained before by natural fermentation: acetoacetyl-pyrrothine, hydroxybutyryl-pyrrothine, and dimethyl Thiolutin (holomycin). Two acyltransferase activities, acetyltransferase and benzoyltransferase catalyzing the incorporation of linear and cyclic acyl groups to the pyrrothine core, respectively, were biochemically characterized in this crude extract. The first one is responsible for formation of acetyl-pyrrothine and the second for benzoyl-pyrrothine. Both enzymes were sensitive to temperature changes: For example, the loss of acetyltransferase and benzoyltransferase activity was 53% and 80% respectively after pre-incubation of crude extract for 60 min at 20°C. The two enzymes were more active in neutral and basal media (pH 7-10) than in the acidic one (pH 3-6). The optimum temperature and pH of acetyltransferase were 40°C and 7, with a Km value of 7.9 μM and a Vmax of 0.63 μM/min when acetyl-CoA was used as limited substrate. Benzoyltransferase had a temperature and a pH optimum at 55°C and 9, a Km value of 14.7 μM, and a Vmax of 0.67 μM/min when benzoyl- CoA was used as limited substrate.
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effect of amino acids containing sulfur on dithiolopyrrolone antibiotic productions by saccharothrix algeriensis nrrl b 24137
Journal of Applied Microbiology, 2006Co-Authors: Noureddine Bouras, Florence Mathieu, Nasserdine Sabaou, Ahmed LebrihiAbstract:Aims: To study the effect of sulfur-containing amino acids (L-cysteine, L-cystine, L-methionine and DL-ethionine) on the production of dithiolopyrrolone antibiotics by Saccharothrix algeriensis NRRL B-24137. Methods and Results: The production levels of dithiolopyrrolones were investigated by using high performance liquid chromatography in a chemically semi-synthetic medium. The production of the studied antibiotics depends upon the nature, concentration and the time of addition of these sources in the culture medium. Both cysteine and cystine favoured the specific productions of dithiolopyrrolones; iso-butyryl-pyrrothine (ISP) by cysteine, however butanoyl-pyrrothine, senecioyl-pyrrothine and tigloyl-pyrrothine by cystine, when added initially to the culture medium. The maximum specific productions of dithiolopyrrolones were observed in the presence of 5 mmol l−1 cystine for Thiolutin, 5 mmol l−1 cysteine for ISP, and 10 mmol l−1 cystine for others studied dithiolopyrrolones as shown in Fig. 3. The production of these antibiotics was decreased when the concentrations of cysteine and cystine were in excess. All dithiolopyrrolone specific productions were strongly inhibited by addition of methionine and ethionine, without inhibition of mycelial growth. Figure 3. Effect of cysteine () and cystine () addition at different concentrations on specific production of Thiolutin (a), senecioyl-pyrrothine (b), tigloyl-pyrrothine (c), iso-butyryl-pyrrothine (d) and butanoyl-pyrrothine (e). Specific dithiolopyrrolone productions are given as mg per g of biomass at the time of maximal productions during 96 h of fermentation. Download figure to PowerPoint Conclusions: Among all studied amino acids, cystine and cysteine can be used as supplements for improvement the production of dithiolopyrrolone antibiotics by S. algeriensis NRRL B-24137. Significance and Impact of the Study: Dithiolopyrrolone antibiotics have many important applications for employing them as medicaments, particularly in the treatment of human and animal cancers. In the present work, the influence of containing-sulfur amino acids on dithiolopyrrolone antibiotic productions was studied. The obtained results can be employed for the optimization of the culture medium for the dithiolopyrrolone productions in higher quantities.
Shiaw-lin Wu - One of the best experts on this subject based on the ideXlab platform.
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Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton
Cell Stress and Chaperones, 2010Co-Authors: Shiaw-lin Wu, Lyndsay Field, Bixi Zeng, Russell W Bandle, John M Sipes, Ramani Ramchandran, Lisa A. Ridnour, David A. Wink, Jeffrey Scott Isenberg, Barry L. KargerAbstract:Thiolutin is a dithiole synthesized by Streptomyces sp. that inhibits endothelial cell adhesion and tumor growth. We show here that Thiolutin potently inhibits developmental angiogenesis in zebrafish and vascular outgrowth from tissue explants in 3D cultures. Thiolutin is a potent and selective inhibitor of endothelial cell adhesion accompanied by rapid induction of HSPB1 (Hsp27) phosphorylation. The inhibitory effects of Thiolutin on endothelial cell adhesion are transient, potentially due to a compensatory increase in Hsp27 protein levels. Accordingly, heat shock induction of Hsp27 limits the anti-adhesive activity of Thiolutin. Thiolutin treatment results in loss of actin stress fibers, increased cortical actin as cells retract, and decreased cellular F-actin. Mass spectrometric analysis of Hsp27 binding partners following immunoaffinity purification identified several regulatory components of the actin cytoskeleton that associate with Hsp27 in a Thiolutin-sensitive manner including several components of the Arp2/3 complex. Among these, ArpC1a is a direct binding partner of Hsp27. Thiolutin treatment induces peripheral localization of phosphorylated Hsp27 and Arp2/3. Hsp27 also associates with the intermediate filament components vimentin and nestin. Thiolutin treatment specifically ablates Hsp27 interaction with nestin and collapses nestin filaments. These results provide new mechanistic insights into regulation of cell adhesion and cytoskeletal dynamics by Hsp27.
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comprehensive characterization of heat shock protein 27 phosphorylation in human endothelial cells stimulated by the microbial dithiole Thiolutin
Journal of Proteome Research, 2008Co-Authors: Shiaw-lin Wu, Russell W Bandle, Lisa A. Ridnour, David A. Wink, Jeffrey S Isenberg, David D Roberts, Barry L. KargerAbstract:Thiolutin is a sulfur-based microbial compound with known activity as an angiogenesis inhibitor. Relative to previously studied angiogenesis inhibitors, Thiolutin is a remarkably potent inducer of heat shock protein 27 (Hsp27) phosphorylation. This phosphorylation requires p38 kinase but is independent of increased p38 phosphorylation. To elucidate how Thiolutin regulates Hsp27 phosphorylation and ultimately angiogenesis, Hsp27 was immunoprecipitated using nonphosphorylated and phospho-Ser78 specific antibodies from lysates of Thiolutin treated and untreated human umbilical vein endothelial cells and analyzed by LC–MS. Separate LC–MS analyses of Lys-C, Lys-C plus trypsin, and Lys-C plus Glu-C digests provided 100% sequence coverage, including the identification of a very large 13 kDa Lys-C fragment using a special sample handling procedure (4 M guanidine HCl) prior to the LC–MS analysis to improve the large peptide recovery. The analysis revealed a novel post-translational modification of Hsp27 involving truncation of the N-terminal Met and acetylation of the penultimate Thr. Analysis of a Glu-C fragment containing two phosphorylation sites, Ser78 and Ser82, and a tryptic fragment containing the other phosphorylation site, Ser15, enabled quantitative stoichiometry of Hsp27 phosphorylation by LC–MS. The strategy revealed details of Hsp27 phosphorylation, including significant di-phosphorylation at both Ser78 and Ser82, that would be difficult to obtain by traditional approaches because oligomerization of the hydrophobic N-terminal region of the molecule prevents efficient enzymatic cleavage. The combination of Western blotting, immunoprecipation, and LC–MS provides a quantitative analysis of Thiolutin-stimulated Hsp27 phosphorylation and further defines the role of Hsp27 in the antiangiogenic activities of Thiolutin and related dithiolethiones.
Hai Deng - One of the best experts on this subject based on the ideXlab platform.
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identification and characterization of the biosynthetic gene cluster of Thiolutin a tumor angiogenesis inhibitor in saccharothrix algeriensis nrrl b 24137
Anti-cancer Agents in Medicinal Chemistry, 2015Co-Authors: Sheng Huang, Ming Him Tong, Zhiwei Qin, Zixin Deng, Hai DengAbstract:In this study, a new dithiolopyrrolone biosynthetic pathway was identified in Saccharothrix algeriensis NRRL B-24137, which was reported to produce a variety of dithiolopyrrolone natural products including Thiolutin, a potential drug candidate for tumor angiogenesis inhibition. Bioinformatics analysis of the cluster revealed that it contains all the essential genes for holothin core biosynthesis and several other auxiliary genes. Interestingly, heterologous expression of the gene cluster in Streptomyces albus only induced the production of holomycin, implying that the gene responsible for the N4-methylation and the gene(s) involved in the formation of various acylated chains on N7 position of the holothin may locate outside the gene cluster. Incubation of holomycin with S-adenosyl-L-methionine (SAM) in the cell-free extract of Sa. algeriensis resulted in the production of Thiolutin, suggesting that the N4-methyl group of Thiolutin is originated from SAM, and the N4-methylation could be in the late stage of biosynthesis of Thiolutin type dithiolopyrrolones. An evolution-based model for biosynthesis of Thiolutin and its analogs was further proposed based on these results.
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Dithiolopyrrolone Natural Products: Isolation, Synthesis and Biosynthesis
MDPI AG, 2013Co-Authors: Zhiwei Qin, Sheng Huang, Hai DengAbstract:Dithiolopyrrolones are a class of antibiotics that possess the unique pyrrolinonodithiole (4H-[1,2] dithiolo [4,3-b] pyrrol-5-one) skeleton linked to two variable acyl groups. To date, there are approximately 30 naturally occurring dithiolopyrrolone compounds, including holomycin, Thiolutin, and aureothricin, and more recently thiomarinols, a unique class of hybrid marine bacterial natural products containing a dithiolopyrrolone framework linked by an amide bridge with an 8-hydroxyoctanoyl chain linked to a monic acid. Generally, dithiolopyrrolone antibiotics have broad-spectrum antibacterial activity against various microorganisms, including Gram-positive and Gram-negative bacteria, and even parasites. Holomycin appeared to be active against rifamycin-resistant bacteria and also inhibit the growth of the clinical pathogen methicillin-resistant Staphylococcus aureus N315. Its mode of action is believed to inhibit RNA synthesis although the exact mechanism has yet to be established in vitro. A recent work demonstrated that the fish pathogen Yersinia ruckeri employs an RNA methyltransferase for self-resistance during the holomycin production. Moreover, some dithiolopyrrolone derivatives have demonstrated promising antitumor activities. The biosynthetic gene clusters of holomycin have recently been identified in S. clavuligerus and characterized biochemically and genetically. The biosynthetic gene cluster of thiomarinol was also identified from the marine bacterium Pseudoalteromonas sp. SANK 73390, which was uniquely encoded by two independent pathways for pseudomonic acid and pyrrothine in a novel plasmid. The aim of this review is to give an overview about the isolations, characterizations, synthesis, biosynthesis, bioactivities and mode of action of this unique family of dithiolopyrrolone natural products, focusing on the period from 1940s until now