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Marine Drugs Aug 2018Over the last two decades, halophilic (organisms that thrive at high salt concentrations) and halotolerant (organisms that have adapted to high salt concentrations)... (Review)
Review
Over the last two decades, halophilic (organisms that thrive at high salt concentrations) and halotolerant (organisms that have adapted to high salt concentrations) myxobacteria emerged as an important source of structurally diverse secondary metabolites from the marine environment. This review explores the advance of metagenomics analysis and 16S rRNA gene phylogeny of the cultured and uncultured myxobacteria from marine and other salt-environments up to July 2018. The diversity of novel groups of myxobacteria in these environments appears unprecedented, especially in the and suborders. The related clade in the suborder seems more widely distributed compared to the exclusively marine myxobacterial cluster. Some of the previously identified clones from metagenomic studies were found to be related to the suborder. This understanding provides the foundation for a vital, unexplored resource. Understanding the conditions required to cultivate these yet "uncultured" myxobacteria in the laboratory, while a key next step, offers a significant potential to further expand access to diverse secondary metabolites.
Topics: Aquatic Organisms; Biodiversity; Biological Products; DNA, Bacterial; Metagenomics; Myxococcales; Phylogeny; RNA, Ribosomal, 16S; Salt Tolerance; Sequence Analysis, DNA
PubMed: 30158489
DOI: 10.3390/md16090303 -
ChemMedChem Jul 2021Natural products provide important lead structures for development of pharmaceutical agents or present attractive tools for medicinal chemistry. However, structurally... (Review)
Review
Natural products provide important lead structures for development of pharmaceutical agents or present attractive tools for medicinal chemistry. However, structurally complex and thus less accessible metabolites defying conventional drug-like properties, as expressed by Pfizer's rule of five, have received less attention as medicinal leads. Traditionally, research focus has been on realizing total syntheses rather than developing more readily available analogs to resolve the critical supply issue. However, very recent studies with complex myxobacterial polyketides have demonstrated that considerable structural simplification may be realized with retention of biological potencies. The context, underlying rationale and importance of tailored synthetic strategies of three such case studies are presented, which may inspire further related activities and may eventually help exploiting the largely untapped biological potential of complex metabolites in general.
Topics: Biological Products; Drug Design; Humans; Molecular Structure; Myxococcales; Polyketides
PubMed: 33755304
DOI: 10.1002/cmdc.202100150 -
Molecular Microbiology Apr 2003A recurring theme in morphogenesis is the coupling of the expression of genes that drive morphogenesis and the morphogenetic process per se. This coupling ensures that... (Review)
Review
A recurring theme in morphogenesis is the coupling of the expression of genes that drive morphogenesis and the morphogenetic process per se. This coupling ensures that gene expression and morphogenesis are carried out in synchrony. Morphogenesis of the spore-filled fruiting bodies in Myxococcus xanthus illustrates this coupling in the construction of a multicellular structure. Fruiting body formation involves two stages: aggregation of cells into mounds and the position-specific sporulation of cells that have accumulated inside mounds. Developmental gene expression propels these two processes. In addition, gene expression in individual cells is adjusted according to their spatial position. Progress in the understanding of the cell surface-associated C-signal is beginning to reveal the framework of an intercellular signalling system that allows the coupling of gene expression and multicellular morphogenesis. Accumulation of the C-signal is tightly regulated and involves transcriptional activation of the csgA gene and proteolysis of the full-length CsgA protein to produce the shorter cell surface-associated 17 kDa C-signal protein. The C-signal induces aggregation, sporulation and developmental gene expression at specific thresholds. The ordered increase in C-signalling levels, in combination with the specific thresholds, allows the C-signal to induce these three processes in the correct temporal order. The contact-dependent C-signal transmission mechanism, in turn, guarantees that C-signalling levels reflect the spatial position of individual cells relative to other cells and, thus, allows the cells to decode their spatial position during morphogenesis. By this mechanism, individual cells can tailor their gene expression profile to one that matches their spatial position. In this scheme, the molecular device that keeps gene expression in individual cells in register with morphogenesis is the C-signalling system, and the morphological structure, which is assessed, is the spatial position of individual cells relative to that of other cells.
Topics: Gene Expression Regulation, Bacterial; Gene Expression Regulation, Developmental; Genes, Bacterial; Myxococcus xanthus
PubMed: 12657040
DOI: 10.1046/j.1365-2958.2003.03399.x -
Microbial Physiology 2021Bacterial predation is a ubiquitous and fundamental biological process, which influences the community composition of microbial ecosystems. Among the best characterised... (Review)
Review
The Genetics of Prey Susceptibility to Myxobacterial Predation: A Review, Including an Investigation into Pseudomonas aeruginosa Mutations Affecting Predation by Myxococcus xanthus.
Bacterial predation is a ubiquitous and fundamental biological process, which influences the community composition of microbial ecosystems. Among the best characterised bacterial predators are the myxobacteria, which include the model organism Myxococcus xanthus. Predation by M. xanthus involves the secretion of antibiotic metabolites and hydrolytic enzymes, which results in the lysis of prey organisms and release of prey nutrients into the extracellular milieu. Due to the generalist nature of this predatory mechanism, M. xanthus has a broad prey range, being able to kill and consume Gram-negative/positive bacteria and fungi. Potential prey organisms have evolved a range of behaviours which protect themselves from attack by predators. In recent years, several investigations have studied the molecular responses of a broad variety of prey organisms to M. xanthus predation. It seems that the diverse mechanisms employed by prey belong to a much smaller number of general "predation resistance" strategies. In this mini-review, we present the current state of knowledge regarding M. xanthus predation, and how prey organisms resist predation. As previous molecular studies of prey susceptibility have focussed on individual genes/metabolites, we have also undertaken a genome-wide screen for genes of Pseudomonas aeruginosa which contribute to its ability to resist predation. P. aeruginosa is a World Health Organisation priority 1 antibiotic-resistant pathogen. It is metabolically versatile and has an array of pathogenic mechanisms, leading to its prevalence as an opportunistic pathogen. Using a library of nearly 5,500 defined transposon insertion mutants, we screened for "prey genes", which when mutated allowed increased predation by a fluorescent strain of M. xanthus. A set of candidate "prey proteins" were identified, which shared common functional roles and whose nature suggested that predation resistance by P. aeruginosa requires an effective metal/oxidative stress system, an intact motility system, and mechanisms for de-toxifying antimicrobial peptides.
Topics: Animals; Ecosystem; Mutation; Myxococcales; Myxococcus xanthus; Predatory Behavior; Pseudomonas aeruginosa
PubMed: 33794538
DOI: 10.1159/000515546 -
Microbiological Reviews Dec 1990Myxobacteria are soil bacteria whose unusually social behavior distinguishes them from other groups of procaryotes. Perhaps the most remarkable aspect of their social... (Review)
Review
Myxobacteria are soil bacteria whose unusually social behavior distinguishes them from other groups of procaryotes. Perhaps the most remarkable aspect of their social behavior occurs during development, when tens of thousands of cells aggregate and form a colorful fruiting body. Inside the fruiting body the vegetative cells convert into dormant, resistant myxospores. However, myxobacterial social behavior is not restricted to the developmental cycle, and three other social behaviors have been described. Vegetative cells have a multigene social motility system in which cell-cell contact is essential for gliding in multicellular swarms. Cell growth on protein is cooperative in that the growth rate increases with the cell density. Rippling is a periodic behavior in which the cells align themselves in ridges and move in waves. These social behaviors indicate that myxobacterial colonies are not merely collections of individual cells but are societies in which cell behavior is synchronized by cell-cell interactions. The molecular basis of these social behaviors is becoming clear through the use of a combination of behavioral, biochemical, and genetic experimental approaches.
Topics: Base Sequence; Biological Evolution; DNA, Bacterial; Molecular Sequence Data; Myxococcales; Nucleic Acid Conformation; RNA, Bacterial
PubMed: 1708086
DOI: 10.1128/mr.54.4.473-501.1990 -
Drugs in R&D 2008The epothilones are a novel class of antineoplastic agents possessing antitubulin activity. The compounds were originally identified as secondary metabolites produced by... (Review)
Review
The epothilones are a novel class of antineoplastic agents possessing antitubulin activity. The compounds were originally identified as secondary metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. Two major compounds, epothilone A and epothilone B, were purified from the S. cellulosum strain So ce90 and their structures were identified as 16-member macrolides. Initial screening with these compounds revealed a very narrow and selective antifungal activity against the zygomycete, Mucor hiemalis. In addition, strong cytotoxic activity against eukaryotic cells, mouse L929 fibroblasts and human T-24 bladder carcinoma cells was observed. Subsequent studies revealed that epothilones induce tubulin polymerization and enhance microtubule stability. Epothilone-induced stabilisation of microtubules was shown to cause arrest at the G2/M transition of the cell cycle and apoptosis. The compounds are active against cancer cells that have developed resistance to taxanes as a result of acquisition of beta-tubulin overexpression or mutations and against multidrug-resistant cells that overexpress P-glycoprotein or multidrug resistance-associated protein. Thus, epothilones represent a new class of antimicrotubule agents with low susceptibility to key tumour resistance mechanisms. More recently, a range of synthetic and semisynthetic epothilone analogues have been produced to further improve the adverse effect profile (or therapeutic window) and to maximize pharmacokinetic and antitumour properties. Various epothilone analogues have demonstrated activity against many tumour types in preclinical studies and several compounds have been and still are being evaluated in clinical trials. This article reviews the identification and early molecular characterization of the epothilones, which has provided insight into the mode of action of these novel antitumour agents in vivo.
Topics: Animals; Antineoplastic Agents; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Humans; Myxococcales; Tubulin Modulators
PubMed: 18095749
DOI: 10.2165/00126839-200809010-00001 -
MBio Feb 2019Self-recognition underlies sociality in many group-living organisms. In bacteria, cells use various strategies to recognize kin to form social groups and, in some cases,...
Self-recognition underlies sociality in many group-living organisms. In bacteria, cells use various strategies to recognize kin to form social groups and, in some cases, to transition into multicellular life. One strategy relies on a single genetic locus that encodes a variable phenotypic tag ("greenbeard") for recognizing other tag bearers. Previously, we discovered a polymorphic cell surface receptor called TraA that directs self-identification through homotypic interactions in the social bacterium Recognition by TraA leads to cellular resource sharing in a process called outer membrane exchange (OME). A second gene in the operon, , is also required for OME but is not involved in recognition. Our prior studies of TraA identified only six recognition groups among closely related isolates. Here we hypothesize that the number of polymorphisms and, consequently, the diversity of recognition in wild isolates are much greater. To test this hypothesis, we expand the scope of TraA characterization to the order From genomic sequences within the three suborders of , we identified 90 orthologs. Sequence analyses and functional characterization of loci suggest that OME is well maintained among diverse myxobacterial taxonomic groups. Importantly, TraA orthologs are highly polymorphic within their variable domain, the region that confers selectivity in self-recognition. We experimentally defined 10 distinct recognition groups and, based on phylogenetic and experimental analyses, predicted >60 recognition groups among the 90 alleles. Taken together, our findings revealed a widespread greenbeard locus that mediates the diversity of self-recognition across the order Many biological species distinguish self from nonself by using different mechanisms. Higher animals recognize close kin via complex processes that often involve the five senses, cognition, and learning, whereas some microbes achieve self-recognition simply through the activity of a single genetic locus. Here we describe a single locus, , in myxobacteria that governs cell-cell recognition within natural populations. We found that is widespread across the order TraA is highly polymorphic among diverse myxobacterial isolates, and such polymorphisms determine selectivity in self-recognition. Through bioinformatic and experimental analyses, we showed that governs many distinct recognition groups within This report provides an example in which a single locus influences social recognition across a wide phylogenetic range of natural populations.
Topics: Bacterial Outer Membrane Proteins; Computational Biology; Data Mining; Genome, Bacterial; Microbial Interactions; Myxococcales; Polymorphism, Genetic; Sequence Homology
PubMed: 30755513
DOI: 10.1128/mBio.02751-18 -
Molecules (Basel, Switzerland) Mar 2023The hard-to-culture slightly halophilic myxobacterium "" SMH-27-4 produces antifungal cyclodepsipeptide miuraenamide A (). Herein, the region (85.9 kbp) containing the...
The hard-to-culture slightly halophilic myxobacterium "" SMH-27-4 produces antifungal cyclodepsipeptide miuraenamide A (). Herein, the region (85.9 kbp) containing the biosynthetic gene cluster (BGC) coding the assembly of was identified and heterologously expressed in A biosynthetic pathway proposed using in silico analysis was verified through the gene disruption of the heterologous transformant. In addition to the core polyketide synthase (PKS) and nonribosomal peptide synthase (NRPS) genes, tyrosine halogenase and -methyltransferase genes participated in the biosynthesis of as their gene-disrupted mutants produced a new congener, debromomiuraenamide A (), and a previously isolated congener, miuraenamide E (), respectively. Multigene disruption provided a heterologous mutant that produced with the highest yield among the prepared mutants. When fed on 3-bromo-L-tyrosine, this mutant produced more in the yield of 1.21 mg/L, which was 20 times higher than that produced by the initially prepared heterologous transformant. Although this yield was comparable to that of the original producer SMH-27-4 (1 mg/L), the culture time was 4.5 times shorter than that of SMH-27-4, indicating a five-fold efficiency in productivity. The results indicate the great potential of the miuraenamide BGC for the future contribution to drug development through logical gene manipulation.
Topics: Anti-Bacterial Agents; Myxococcales; Depsipeptides; Polyketide Synthases; Multigene Family
PubMed: 36985787
DOI: 10.3390/molecules28062815 -
Science Advances Feb 2023The predatory deltaproteobacterium Myxococcus xanthus uses a helically-trafficked motor at bacterial focal-adhesion (bFA) sites to power gliding motility. Using total...
The predatory deltaproteobacterium Myxococcus xanthus uses a helically-trafficked motor at bacterial focal-adhesion (bFA) sites to power gliding motility. Using total internal reflection fluorescence and force microscopies, we identify the von Willebrand A domain-containing outer-membrane (OM) lipoprotein CglB as an essential substratum-coupling adhesin of the gliding transducer (Glt) machinery at bFAs. Biochemical and genetic analyses reveal that CglB localizes to the cell surface independently of the Glt apparatus; once there, it is recruited by the OM module of the gliding machinery, a heteroligomeric complex containing the integral OM β barrels GltA, GltB, and GltH, as well as the OM protein GltC and OM lipoprotein GltK. This Glt OM platform mediates the cell-surface accessibility and retention of CglB by the Glt apparatus. Together, these data suggest that the gliding complex promotes regulated surface exposure of CglB at bFAs, thus explaining the manner by which contractile forces exerted by inner-membrane motors are transduced across the cell envelope to the substratum.
Topics: Myxococcales; Focal Adhesions; Adhesins, Bacterial; Bacterial Adhesion; Lipoproteins; Bacterial Proteins
PubMed: 36812310
DOI: 10.1126/sciadv.abq0619 -
Molecules (Basel, Switzerland) Feb 2018Two new secondary metabolites, labindole A [2-methyl-3-(2-nitroethyl)-3H-indole] () and labindole B [2-methyl-3-(2-nitrovinyl)-3H-indole] (), were isolated from the...
Two new secondary metabolites, labindole A [2-methyl-3-(2-nitroethyl)-3H-indole] () and labindole B [2-methyl-3-(2-nitrovinyl)-3H-indole] (), were isolated from the myxobacterium (DSM 27648). Additionally, four metabolites , , and already known from other sources were obtained. Their structures were elucidated from high resolution electrospray ionisation mass spectrometry (HRESIMS) and 1D and 2D nuclear magnetic resonance (NMR) spectroscopy data and their relative configuration was assigned based on nuclear Overhauser effect (NOE) and vicinal ¹H-NMR coupling data. The compounds where tested for biological activities; labindoles A () and B () exhibited significant activity against Hepatitis C Virus, 9-carbazole (), 3-chloro-9-carbazole () and 4-hydroxymethyl-quinoline () showed antifungal activities. Moreover, compound had weak to moderate antibacterial activities, while labindoles A () and B () were devoid of significant antifungal and antibacterial effects.
Topics: Anti-Infective Agents; Antiviral Agents; Biological Products; Fermentation; Hepacivirus; Heterocyclic Compounds; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Molecular Structure; Myxococcales; Secondary Metabolism
PubMed: 29495640
DOI: 10.3390/molecules23030542