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FEMS Microbiology Reviews Jul 2010Bacteria can utilize signal molecules to coordinate their behavior to survive in dynamic multispecies communities. Indole is widespread in the natural environment, as a... (Review)
Review
Bacteria can utilize signal molecules to coordinate their behavior to survive in dynamic multispecies communities. Indole is widespread in the natural environment, as a variety of both Gram-positive and Gram-negative bacteria (to date, 85 species) produce large quantities of indole. Although it has been known for over 100 years that many bacteria produce indole, the real biological roles of this molecule are only now beginning to be unveiled. As an intercellular signal molecule, indole controls diverse aspects of bacterial physiology, such as spore formation, plasmid stability, drug resistance, biofilm formation, and virulence in indole-producing bacteria. In contrast, many non-indole-producing bacteria, plants and animals produce diverse oxygenases which may interfere with indole signaling. It appears indole plays an important role in bacterial physiology, ecological balance, and possibly human health. Here we discuss our current knowledge and perspectives on indole signaling.
Topics: Bacteria; Bacterial Physiological Phenomena; Biofilms; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Indoles; Plasmids; Quorum Sensing; Signal Transduction; Virulence
PubMed: 20070374
DOI: 10.1111/j.1574-6976.2009.00204.x -
Gut Microbes Nov 2020Commensal microbiota-dependent tryptophan catabolism within the gastrointestinal tract is known to exert profound effects upon host physiology, including the maintenance...
Commensal microbiota-dependent tryptophan catabolism within the gastrointestinal tract is known to exert profound effects upon host physiology, including the maintenance of epithelial barrier and immune function. A number of abundant microbiota-derived tryptophan metabolites exhibit activation potential for the aryl hydrocarbon receptor (AHR). Gene expression facilitated by AHR activation through the presence of dietary or microbiota-generated metabolites can influence gastrointestinal homeostasis and confer protection from intestinal challenges. Utilizing untargeted mass spectrometry-based metabolomics profiling, combined with AHR activity screening assays, we identify four previously unrecognized tryptophan metabolites, present in mouse cecal contents and human stool, with the capacity to activate AHR. Using GC/MS and LC/MS platforms, quantification of these novel AHR activators, along with previously established AHR-activating tryptophan metabolites, was achieved, providing a relative order of abundance. Using physiologically relevant concentrations and quantitative gene expression analyses, the relative efficacy of these tryptophan metabolites with regard to mouse or human AHR activation potential is examined. These data reveal indole, 2-oxindole, indole-3-acetic acid and kynurenic acid as the dominant AHR activators in mouse cecal contents and human stool from participants on a controlled diet. Here we provide the first documentation of the relative abundance and AHR activation potential of a panel of microbiota-derived tryptophan metabolites. Furthermore, these data reveal the human AHR to be more sensitive, at physiologically relevant concentrations, to tryptophan metabolite activation than mouse AHR. Additionally, correlation analyses indicate a relationship linking major tryptophan metabolite abundance with AHR activity, suggesting these cecal/fecal metabolites represent biomarkers of intestinal AHR activity.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cecum; Diet; Feces; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Indoleacetic Acids; Indoles; Kynurenic Acid; Mice; Mice, Inbred C57BL; Receptors, Aryl Hydrocarbon; Signal Transduction; Tryptophan
PubMed: 32783770
DOI: 10.1080/19490976.2020.1788899 -
Molecules (Basel, Switzerland) Nov 2016Indole phytoalexins from crucifers have been shown to exhibit significant anti-cancer, chemopreventive, and antiproliferative activity. Phytoalexins are natural low... (Review)
Review
Indole phytoalexins from crucifers have been shown to exhibit significant anti-cancer, chemopreventive, and antiproliferative activity. Phytoalexins are natural low molecular antimicrobial compounds that are synthesized and accumulated in plants after their exposure to pathogenic microorganisms. Most interestingly, crucifers appear to be the only plant family producing sulfur-containing indole phytoalexins. The mechanisms underlying its anti-cancer properties are unknown. Isolation from cruciferous plants does not provide sufficient quantities of indole phytoalexins and, for biological screening, they are usually obtainable through synthesis. Understanding the molecular mechanism of the action of these substances and their structure-activity relationships is quite important in the development of new analogs with a more favorable profile of biological activities. In this review, we present the key features of indole phytoalexins, mainly their antiproliferative ativities.
Topics: Brassicaceae; Cell Proliferation; Humans; Indoles; Molecular Structure; Sesquiterpenes; Tumor Cells, Cultured; Phytoalexins
PubMed: 27898039
DOI: 10.3390/molecules21121626 -
The Plant Journal : For Cell and... Apr 2021The maize (Zea mays) genome encodes three indole-3-glycerolphosphate synthase enzymes (IGPS1, 2, and 3) catalyzing the conversion of...
The maize (Zea mays) genome encodes three indole-3-glycerolphosphate synthase enzymes (IGPS1, 2, and 3) catalyzing the conversion of 1-(2-carboxyphenylamino)-l-deoxyribulose-5-phosphate to indole-3-glycerolphosphate. Three further maize enzymes (BX1, benzoxazinoneless 1; TSA, tryptophan synthase alpha subunit; and IGL, indole glycerolphosphate lyase) convert indole-3-glycerolphosphate to indole, which is released as a volatile defense signaling compound and also serves as a precursor for the biosynthesis of tryptophan and defense-related benzoxazinoids. Phylogenetic analyses showed that IGPS2 is similar to enzymes found in both monocots and dicots, whereas maize IGPS1 and IGPS3 are in monocot-specific clades. Fusions of yellow fluorescent protein with maize IGPS enzymes and indole-3-glycerolphosphate lyases were all localized in chloroplasts. In bimolecular fluorescence complementation assays, IGPS1 interacted strongly with BX1 and IGL, IGPS2 interacted primarily with TSA, and IGPS3 interacted equally with all three indole-3-glycerolphosphate lyases. Whereas IGPS1 and IGPS3 expression was induced by insect feeding, IGPS2 expression was not. Transposon insertions in IGPS1 and IGPS3 reduced the abundance of both benzoxazinoids and free indole. Spodoptera exigua (beet armyworm) larvae show improved growth on igps1 mutant maize plants. Together, these results suggest that IGPS1 and IGPS3 function mainly in the biosynthesis of defensive metabolites, whereas IGPS2 may be involved in the biosynthesis of tryptophan. This metabolic channeling is similar to, though less exclusive than, that proposed for the three maize indole-3-glycerolphosphate lyases.
Topics: Benzoxazines; Indole-3-Glycerol-Phosphate Synthase; Indoles; Tryptophan; Zea mays
PubMed: 33458870
DOI: 10.1111/tpj.15163 -
Drug Design, Development and Therapy 2020Malaria remains a global public health problem due to the uphill fight against the causative parasites that are relentless in developing resistance. Indole-based... (Review)
Review
Malaria remains a global public health problem due to the uphill fight against the causative parasites that are relentless in developing resistance. Indole-based antiplasmodial compounds are endowed with multiple modes of action, of which inhibition of hemozoin formation is the major mechanism of action reported for compounds such as cryptolepine, flinderoles, and isosungucine. Indole-based compounds exert their potent activity against chloroquine-resistant strains by inhibiting hemozoin formation in a mode of action different from that of chloroquine or through a novel mechanism of action. For example, dysregulating the sodium and osmotic homeostasis of through inhibition of PfATP4 is the novel mechanism of cipargamin. The potential of developing multi-targeted compounds through molecular hybridization ensures the existence of indole-based compounds in the antimalarial pipeline.
Topics: Antimalarials; Calcium-Transporting ATPases; Enzyme Inhibitors; Humans; Indoles; Malaria, Falciparum; Parasitic Sensitivity Tests; Plasmodium falciparum
PubMed: 33204071
DOI: 10.2147/DDDT.S278588 -
Molecules (Basel, Switzerland) Feb 2023Sclareolide is a sesquiterpene lactone isolated from various plant sources in tons every year and is commercially used as a flavor ingredient in the cosmetic and food...
Sclareolide is a sesquiterpene lactone isolated from various plant sources in tons every year and is commercially used as a flavor ingredient in the cosmetic and food industries. Antitumor and antiviral activities of sclareolide have been previously reported. However, biological studies of sclareolide synthetic analogous are few. In view of these, we developed a robust synthetic method that allows the assembly of 36 novel sclareolide-indole conjugates and their derivatives. The synthetic method was based on TiCl-promoted nucleophilic substitution of sclareolide-derived hemiacetal , while electron-rich aryles including indoles, polyphenol ethers, and pyrazolo [1,5-a]pyridine were good substrates. The stereochemistry of the final products was confirmed by single-crystal X-ray diffraction analysis, while the antiproliferative activities of selected final products were tested in K562 and MV4-11 cancer cell lines. Cytometric flow analysis shows that lead compounds - and -induced robust apoptosis in MV4-11 cancer cells, while they exhibited weak impact on cell cycle progression. Taken together, our study suggests that sclareolide could be a good template and substrate for the synthesis of novel antiproliferative compounds.
Topics: Antineoplastic Agents; Indoles; Diterpenes; Cell Proliferation; Drug Screening Assays, Antitumor; Molecular Structure; Structure-Activity Relationship; Cell Line, Tumor
PubMed: 36838727
DOI: 10.3390/molecules28041737 -
Cell Reports Jul 2023Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. To explore microbial influences on susceptibility, we...
Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. To explore microbial influences on susceptibility, we screened 85 microbiota-associated metabolites for their effects on Cryptosporidium parvum growth in vitro. We identify eight inhibitory metabolites in three main classes: secondary bile salts/acids, a vitamin B precursor, and indoles. Growth restriction of C. parvum by indoles does not depend on the host aryl hydrocarbon receptor (AhR) pathway. Instead, treatment impairs host mitochondrial function and reduces total cellular ATP, as well as directly reducing the membrane potential in the parasite mitosome, a degenerate mitochondria. Oral administration of indoles, or reconstitution of the gut microbiota with indole-producing bacteria, delays life cycle progression of the parasite in vitro and reduces the severity of C. parvum infection in mice. Collectively, these findings indicate that microbiota metabolites impair mitochondrial function and contribute to colonization resistance to Cryptosporidium infection.
Topics: Animals; Mice; Cryptosporidium parvum; Cryptosporidiosis; Cryptosporidium; Microbiota; Mitochondria; Indoles
PubMed: 37384526
DOI: 10.1016/j.celrep.2023.112680 -
Organic & Biomolecular Chemistry Apr 2013Indole is a heterocycle of great importance to biological systems and materials applications. Synthesis of indole and its derivatives has been a major focus of research... (Review)
Review
Indole is a heterocycle of great importance to biological systems and materials applications. Synthesis of indole and its derivatives has been a major focus of research for over a century. BN/CC isosterism is an emerging strategy for expanding the structural diversity of indole-based compounds. Two classes of BN indoles have been reported to date: the well-studied "external" BN indoles (or 1,3,2-benzodiazaborolines), and the recently reported "fused" BN indoles. This perspective presents the history of both classes of indole isosteres, with a general overview of their synthesis, functionalization, and properties.
Topics: Indoles; Models, Molecular; Molecular Structure; Stereoisomerism
PubMed: 23403937
DOI: 10.1039/c3ob27436e -
Scientific Reports Apr 2022Indole signaling plays an important role in bacterial pathogenesis. In this study, the impact of indole on biofilm formation, swimming and swarming motility were...
Indole signaling plays an important role in bacterial pathogenesis. In this study, the impact of indole on biofilm formation, swimming and swarming motility were explored in Vibrio tasmaniensis LGP32 and Vibrio crassostreae J2-9, two model pathogens of bivalves. The results showed that indole decreased swimming and swarming motility in both strains, and decreased biofilm formation in V. crassostreae J2-9. Furthermore, indole affected a large number of genes at RNA level, including genes related to metabolism, ABC transporters, flagellar assembly, chemotaxis, and response regulators. Finally, the bacterial virulence towards mussel larvae was decreased by pretreatment with indole in both V. tasmaniensis LGP32 and V. crassostreae J2-9. After 5 days, the survival rate of mussel larvae increased 2.4-fold and 2.8-fold in mussel larvae challenged with V. tasmaniensis LGP32 pretreated with 200 µM and 500 µM indole, respectively. The survival rate of mussel larvae increased 1.5-fold and 1.9-fold in mussel larvae challenged with V. crassostreae J2-9 pretreated with 200 µM and 500 µM indole, respectively. These data indicate that indole has a significant impact on the virulence of V. tasmaniensis LGP32 and V. crassostreae J2-9, and indole signaling could be a promising target for antivirulence therapy.
Topics: Animals; Bivalvia; Indoles; Vibrio; Virulence
PubMed: 35388110
DOI: 10.1038/s41598-022-09799-1 -
European Journal of Medicinal Chemistry Jan 2018A novel series of indole and benzimidazole bichalcophene diamidine derivatives were prepared to study their antimicrobial activity against the tropical parasites causing...
A novel series of indole and benzimidazole bichalcophene diamidine derivatives were prepared to study their antimicrobial activity against the tropical parasites causing African sleeping sickness and malaria. The dicyanoindoles needed to synthesize the target diamidines were obtained through Stille coupling reactions while the bis-cyanobenzimidazoles intermediates were made via condensation/cyclization reactions of different aldehydes with 4-cyano-1,2-diaminobenzene. Different amidine synthesis methodologies namely, lithium bis-trimethylsilylamide (LiN[Si(CH3)]) and Pinner methods were used to prepare the diamidines. Both types (indole and benzimidazole) derivatives of the new diamidines bind strongly with the DNA minor groove and generally show excellent in vitro antitrypanosomal activity. The diamidino-indole derivatives also showed excellent in vitro antimalarial activity while their benzimidazole counterparts were generally less active. Compound 7c was highly active in vivo and cured all mice infected with Trypanosoma brucei rhodesiense, a model that mimics the acute stage of African sleeping sickness, at a low dose of 4 × 5 mg/kg i.p. and hence 7c is more potent in vivo than pentamidine.
Topics: Animals; Benzimidazoles; Cell Survival; Disease Models, Animal; Indoles; Mice; Parasitic Sensitivity Tests; Pentamidine; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosomiasis, African
PubMed: 29126729
DOI: 10.1016/j.ejmech.2017.10.056