platensimycin has been researched along with platencin* in 33 studies
8 review(s) available for platensimycin and platencin
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Challenges and opportunities for natural product discovery, production, and engineering in native producers versus heterologous hosts.
Recent advances and emerging technologies for metabolic pathway engineering and synthetic biology have transformed the field of natural product discovery, production, and engineering. Despite these advancements, there remain many challenges in understanding how biosynthetic gene clusters are silenced or activated, including changes in the transcription of key biosynthetic and regulatory genes. This knowledge gap is highlighted by the success and failed attempts of manipulating regulatory genes within biosynthetic gene clusters in both native producers and heterologous hosts. These complexities make the choice of native producers versus heterologous hosts, fermentation medium, and supply of precursors crucial factors in achieving the production of the target natural products and engineering designer analogs. Nature continues to serve as inspiration for filling the knowledge gaps and developing new research strategies. By exploiting the evolutionary power of nature, alternative producers, with the desired genetic amenability and higher titers of the target natural products, and new strains, harboring gene clusters that encode evolutionary optimized congeners of the targeted natural product scaffolds, can be discovered. These newly identified strains can serve as an outstanding biotechnology platform for the engineered production of sufficient quantities of the target natural products and their analogs, enabling biosynthetic studies and potential therapeutic applications. These challenges and opportunities are showcased herein using fredericamycin, iso-migrastatin, platencin and platensimycin, the enediynes of C-1027, tiancimycin, and yangpumicin, and the leinamycin family of natural products. Topics: Adamantane; Aminobenzoates; Aminoglycosides; Aminophenols; Anilides; Bacterial Proteins; Biological Products; Biosynthetic Pathways; Drug Discovery; Enediynes; Gene Expression Regulation, Bacterial; Genes, Bacterial; Lactams; Macrolides; Metabolic Engineering; Multigene Family; Piperidones; Polycyclic Compounds; Protein Conformation; Sequence Analysis, DNA; Streptomyces; Thiazoles; Thiones | 2019 |
Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine.
Natural products have served as the main source of drugs and drug leads, and natural products produced by microorganisms are one of the most prevalent sources of clinical antibiotics. Their unparalleled structural and chemical diversities provide a basis to investigate fundamental biological processes while providing access to a tremendous amount of chemical space. There is a pressing need for novel antibiotics with new mode of actions to combat the growing challenge of multidrug resistant pathogens. This review begins with the pioneering discovery and biological activities of platensimycin (PTM) and platencin (PTN), two antibacterial natural products isolated from Streptomyces platensis. The elucidation of their unique biochemical mode of action, structure-activity relationships, and pharmacokinetics is presented to highlight key aspects of their biological activities. It then presents an overview of how microbial genomics has impacted the field of PTM and PTN and revealed paradigm-shifting discoveries in terpenoid biosynthesis, fatty acid metabolism, and antibiotic and antidiabetic therapies. It concludes with a discussion covering the future perspectives of PTM and PTN in regard to natural products discovery, bacterial diterpenoid biosynthesis, and the pharmaceutical promise of PTM and PTN as antibiotics and for the treatment of metabolic disorders. PTM and PTN have inspired new discoveries in chemistry, biology, enzymology, and medicine and will undoubtedly continue to do so. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Animals; Anti-Infective Agents; Communicable Diseases; Humans; Polycyclic Compounds; Protein Structure, Secondary; Protein Structure, Tertiary; Structure-Activity Relationship | 2017 |
Review of Platensimycin and Platencin: Inhibitors of β-Ketoacyl-acyl Carrier Protein (ACP) Synthase III (FabH).
Platensimycin and platencin were successively discovered from the strain Streptomyces platensis through systematic screening. These natural products have been defined as promising agents for fighting multidrug resistance in bacteria by targeting type II fatty acid synthesis with slightly different mechanisms. Bioactivity studies have shown that platensimycin and platencin offer great potential to inhibit many resistant bacteria with no cross-resistance or toxicity observed in vivo. This review summarizes the general information on platensimycin and platencin, including antibacterial and self-resistant mechanisms. Furthermore, the total synthesis pathways of platensimycin and platencin and their analogues from recent studies are presented. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Fatty Acid Synthase, Type II; Molecular Structure; Polycyclic Compounds; Streptomyces | 2015 |
Platensimycin and its relatives: a recent story in the struggle to develop new naturally derived antibiotics.
Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Biological Products; Drug Design; Drug Resistance, Multiple; Enterococcus faecalis; Methicillin-Resistant Staphylococcus aureus; Polycyclic Compounds; Streptococcus pneumoniae; Structure-Activity Relationship | 2011 |
Platensimycin and platencin: promising antibiotics for future application in human medicine.
Platensimycin and platencin are novel antibiotics produced by Streptomyces platensis. They are potent and non-toxic natural products active against Gram-positive pathogens, including antibiotic-resistant strains and Mycobacterium tuberculosis. They were isolated using an intriguing target-based whole-cell antisense differential sensitivity assay as inhibitors of fatty acid biosynthesis of type II. This type of biosynthesis is not present in humans. Platensimycin inhibits the elongation-condensing enzyme FabF, whereas platencin inhibits both FabF and FabH. For these antibiotics to become successful drugs, their pharmacokinetics must be improved. They have too high a rate of clearance in the body, yielding a low degree of systematic exposure. They work well when administered by continuous infusion, but this is not a useful method of delivery to patients. The two antibiotics and many analogs have been prepared by chemical synthesis. Natural congeners have also been obtained from the producing actinomycete. However, none of these molecules are as active as platensimycin and platencin. Using tools of rational metabolic engineering, superior strains have been produced making hundreds of times more antibiotic than the natural strains. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Fatty Acids; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipid Metabolism; Models, Molecular; Molecular Structure; Polycyclic Compounds; Streptomyces | 2011 |
Improvement of secondary metabolite production in Streptomyces by manipulating pathway regulation.
Titer improvement is a constant requirement in the fermentation industry. The traditional method of "random mutation and screening" has been very effective despite the considerable amount of time and resources it demands. Rational metabolic engineering, with the use of recombinant DNA technology, provides a novel, alternative strategy for titer improvement that complements the empirical method used in industry. Manipulation of the specific regulatory systems that govern secondary metabolite production is an important aspect of metabolic engineering that can efficiently improve fermentation titers. In this review, we use examples from Streptomyces secondary metabolism, the most prolific source of clinically used drugs, to demonstrate the power and utility of exploiting natural regulatory networks, in particular pathway-specific regulators, for titer improvement. Efforts to improve the titers of fredericamycin, C-1027, platensimycin, and platencin in our lab are highlighted. Topics: Adamantane; Aminobenzoates; Aminoglycosides; Aminophenols; Anilides; Anti-Infective Agents; Bacterial Proteins; Biotechnology; Enediynes; Fermentation; Gene Expression Regulation, Bacterial; Genetic Engineering; Polycyclic Compounds; Streptomyces | 2010 |
Discovery and syntheses of "superbug challengers"-platensimycin and platencin.
Bacteria have developed resistance to almost all existing antibiotics known today and this has been a major issue over the last few decades. The search for a new class of antibiotics with a new mode of action to fight these multiply-drug-resistant strains, or "superbugs", allowed a team of scientists at Merck to discover two novel antibiotics, platensimycin and platencin using advanced screening strategies, as inhibitors of bacterial fatty acid biosynthesis, which is essential for the survival of bacteria. Though both these antibiotics are structurally related, they work by slightly different mechanisms and target different enzymes conserved in the bacterial fatty acid biosynthesis. This Focus Review summarizes the synthetic and biological aspects of these natural products and their analogues and congeners. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Infective Agents; Drug Discovery; Drug Resistance, Multiple, Bacterial; Fatty Acid Synthesis Inhibitors; Polycyclic Compounds | 2010 |
Platensimycin: a promising antimicrobial targeting fatty acid synthesis.
Platensimycin was recently discovered by Merck Research Laboratories and has created considerable interest given its potent antibacterial activity and mode of action. The use of RNA gene-silencing techniques and screening libraries of natural products allowed Merck to find this antibiotic which may have otherwise been missed using conventional methods. Interestingly, platensimycin has shown good activity against a panel of Gram positive organisms which included various resistant strains. Platensimycin works by inhibiting beta-ketoacyl synthases I/II (FabF/B) which are key enzymes in the production of fatty acids required for bacterial cell membranes. So far, a number of groups have explored synthetic strategies for platensimycin and this work has subsequently lead to the synthesis of active analogues. Given its mode of action, it is intriguing as to why Merck themselves patented only a single compound and have not apparently sought to generate further libraries. This review will discuss the origins of platensimycin, its mechanism of action, synthetic schemes and where the future may take us following this fascinating discovery. Topics: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; Adamantane; Aminobenzoates; Aminophenols; Anilides; Animals; Anti-Infective Agents; Fatty Acids; Humans; Molecular Structure; Polycyclic Compounds; Structure-Activity Relationship | 2008 |
25 other study(ies) available for platensimycin and platencin
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Rapid, Selective, and Sensitive Method for Semitargeted Discovery of Congeneric Natural Products by Liquid Chromatography Tandem Mass Spectrometry.
Natural product congeners serve a useful role in the understanding of natural product biosynthesis and structure-activity relationships. A minor congener with superior activity, selectivity, and modifiable functional groups could serve as a more effective lead structure and replace even the original lead molecule that was used for medicinal chemistry modifications. Currently, no effective method exists to discover targeted congeners rapidly, specifically, and selectively from producing sources. Herein, a new method based on liquid-chromatography tandem-mass spectrometry combination is evaluated for targeted discovery of congeners of platensimycin and platencin from the extracts of Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Biological Products; Chromatography, Liquid; High-Throughput Screening Assays; Molecular Structure; Polycyclic Compounds; Streptomyces; Structure-Activity Relationship; Tandem Mass Spectrometry | 2021 |
Cryptic and Stereospecific Hydroxylation, Oxidation, and Reduction in Platensimycin and Platencin Biosynthesis.
Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Hydroxylation; Molecular Conformation; Oxidation-Reduction; Polycyclic Compounds; Stereoisomerism | 2019 |
Characterization and Crystal Structure of a Nonheme Diiron Monooxygenase Involved in Platensimycin and Platencin Biosynthesis.
Nonheme diiron monooxygenases make up a rapidly growing family of oxygenases that are rarely identified in secondary metabolism. Herein, we report the in vivo, in vitro, and structural characterizations of a nonheme diiron monooxygenase, PtmU3, that installs a C-5 β-hydroxyl group in the unified biosynthesis of platensimycin and platencin, two highly functionalized diterpenoids that act as potent and selective inhibitors of bacterial and mammalian fatty acid synthases. This hydroxylation sets the stage for the subsequent A-ring cleavage step key to the unique diterpene-derived scaffolds of platensimycin and platencin. PtmU3 adopts an unprecedented triosephosphate isomerase (TIM) barrel structural fold for this class of enzymes and possesses a noncanonical diiron active site architecture with a saturated six-coordinate iron center lacking a μ-oxo bridge. This study reveals the first member of a previously unidentified superfamily of TIM-barrel-fold enzymes for metal-dependent dioxygen activation, with the majority predicted to act on CoA-linked substrates, thus expanding our knowledge of nature's repertoire of nonheme diiron monooxygenases and TIM-barrel-fold enzymes. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Catalytic Domain; Crystallography, X-Ray; Hydroxylation; Iron; Mixed Function Oxygenases; Models, Molecular; Polycyclic Compounds | 2019 |
Biomimetic Stereoselective Sulfa-Michael Addition Leads to Platensimycin and Platencin Sulfur Analogues against Methicillin-Resistant Staphylococcus aureus.
Several sulfur-containing platensimycin (PTM) and platencin (PTN) analogues, with activities comparable to the parent natural products, have recently been discovered from microorganisms, implying a biomimetic route to diversify the PTM and PTN scaffolds for structure-activity relationship study. We present here a substrate-directed and scaleable semisynthetic strategy to make PTM and PTN sulfur analogues with excellent diasteroselectivity, without using any chiral catalysts. Most of the sulfur analogues showed strong activities against clinical Staphylococcus aureus isolates, with minimum inhibitory concentrations of 0.5-2 μg mL Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Biological Products; Biomimetics; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Polycyclic Compounds; Structure-Activity Relationship; Sulfur | 2018 |
Biosynthesis of thiocarboxylic acid-containing natural products.
Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN. We identify a thioacid cassette encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A and sulfur transfer, respectively. ThioPTM and thioPTN bind tightly to β-ketoacyl-ACP synthase II (FabF) and retain strong antibacterial activities. Density functional theory calculations of binding and solvation free energies suggest thioPTM and thioPTN bind to FabF more favorably than PTM and PTN. Additionally, thioacid cassettes are prevalent in the genomes of bacteria, implicating that thiocarboxylic acid-containing natural products are underappreciated. These results suggest that thiocarboxylic acid, as an alternative pharmacophore, and thiocarboxylic acid-containing natural products may be considered for future drug discovery. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Biological Products; Escherichia coli; Multigene Family; Polycyclic Compounds; Streptomyces; Sulfur | 2018 |
In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin.
Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation. We determined that hydrolysis is a viable clearance mechanism in vivo and synthesized two PTM analogues to address in vivo hydrolysis. Urea- and carbamate-PTM analogues showed no detectable hydrolysis in vivo, at the expense of antibacterial activity, with no further improvement in systemic exposure. The antibacterial sulfur-containing analogues PTM D1 and PTM ML14 showed significant decreases in renal clearance. These studies set the stage for continued generation of PTM and PTN analogues in an effort to improve their pharmacokinetics while retaining or improving their biological activities. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Animals; Anti-Bacterial Agents; Carbamates; Carbon-13 Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C57BL; Polycyclic Compounds; Proton Magnetic Resonance Spectroscopy; Urea | 2017 |
Nutritional control of antibiotic production by Streptomyces platensis MA7327: importance of l-aspartic acid.
Streptomyces platensis MA7327 is a bacterium producing interesting antibiotics, which act by the novel mechanism of inhibiting fatty acid biosynthesis. The antibiotics produced by this actinomycete are platensimycin and platencin plus some minor related antibiotics. Platensimycin and platencin have activity against antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus; they also lack toxicity in animal models. Platensimycin also has activity against diabetes in a mouse model. We have been interested in studying the effects of primary metabolites on production of these antibiotics in our chemically defined production medium. In the present work, we tested 32 primary metabolites for their effect. They included 20 amino acids, 7 vitamins and 5 nucleic acid derivatives. Of these, only l-aspartic acid showed stimulation of antibiotic production. We conclude that the stimulatory effect of aspartic acid is due to its role as a precursor involved in the biosynthesis of aspartate-4-semialdehyde, which is the starting point for the biosynthesis of the 3-amino-2,4-dihydroxy benzoic acid portion of the platensimycin molecule. Topics: Adamantane; Amino Acids; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Aspartic Acid; Nucleic Acids; Polycyclic Compounds; Streptomyces; Vitamins | 2017 |
Antibacterial sulfur-containing platensimycin and platencin congeners from Streptomyces platensis SB12029.
The platensimycin (PTM) and platencin (PTN) class of natural products are promising drug leads that target bacterial and mammalian fatty acid synthases. Natural congeners and synthetic analogues of PTM and PTN have been instrumental in determining their structure-activity relationships, with only a few analogues retaining the potencies of PTM and PTN. Here we describe the identification and isolation of two new sulfur-containing PTM congeners (3 and 5) from the engineered dual PTM-PTN overproducing Streptomyces platensis SB12029. Structure elucidation of platensimycin D1 (5), a sulfur-containing PTM pseudo-dimer, revealed the existence of its presumptive thioacid precursor (3). The unstable thioacid 3 was isolated and confirmed by structural characterization of its permethylated product (6). LC-MS analysis of crude extracts of SB12029 confirmed the presence of the thioacid analogue of PTN (4). The minimum inhibitory concentration (MIC) was determined for 5 revealing retention of the strong antibacterial activity of PTM. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Biological Products; Microbial Sensitivity Tests; Micrococcus luteus; Polycyclic Compounds; Staphylococcus aureus; Streptomyces; Sulfur | 2016 |
Titer improvement and pilot-scale production of platensimycin from Streptomyces platensis SB12026.
Platensimycin (PTM) and platencin (PTN), isolated from several strains of Streptomyces platensis are potent antibiotics against multi-drug resistant bacteria. PTM was also shown to have antidiabetic and antisteatotic activities in mouse models. Through a novel genome-mining method, we have recently identified six PTM and PTN dual-producing strains, and generated several mutants with improved production of PTM or PTN by inactivating the pathway-specific transcriptional repressor gene ptmR1. Among them, S. platensis SB12026 gave the highest titer of 310 mg/L for PTM. In this study, we now report titer improvement by medium and fermentation optimization and pilot-scale production and isolation of PTM from SB12026. The fermentation medium optimization was achieved by manipulating the carbon and nitrogen sources, as well as the inorganic salts. The highest titer of 1560 mg/L PTM was obtained in 15-L fermentors, using a formulated medium mainly containing soluble starch, soybean flour, morpholinepropanesulfonic acid sodium salt and CaCO3. In addition, a polyamide chromatographic step was applied to facilitate the purification and 45.14 g of PTM was successfully obtained from a 60 L scale fermentation. These results would speed up the future development of PTM as human medicine. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Bioreactors; Culture Media; Fermentation; Industrial Microbiology; Pilot Projects; Polycyclic Compounds; Streptomyces | 2016 |
A Mutasynthetic Library of Platensimycin and Platencin Analogues.
Inactivation of ptmB1, ptmB2, ptmT2, or ptmC in Streptomyces platensis SB12029, a platensimycin (PTM) and platencin (PTN) overproducer, revealed that PTM and PTN biosynthesis features two distinct moieties that are individually constructed and convergently coupled to afford PTM and PTN. A focused library of PTM and PTN analogues was generated by mutasynthesis in the ΔptmB1 mutant S. platensis SB12032. Of the 34 aryl variants tested, 18 were incorporated with high titers. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Molecular Structure; Polycyclic Compounds; Small Molecule Libraries; Stereoisomerism | 2016 |
A genetically amenable platensimycin- and platencin-overproducer as a platform for biosynthetic explorations: a showcase of PtmO4, a long-chain acyl-CoA dehydrogenase.
Platensimycin (PTM) and platencin (PTN) are members of a new class of promising drug leads that target bacterial and mammalian fatty acid synthases. We previously cloned and sequenced the PTM and PTN gene clusters, discovered six additional PTM-PTN dual producing strains, and demonstrated the dramatic overproduction of PTM and PTN by inactivating the pathway-specific regulators ptmR1 or ptnR1 in five different strains. Our ability to utilize these PTM-PTN dual overproducing strains was limited by their lack of genetic amenability. Here we report the construction of Streptomyces platensis SB12029, a genetically amenable, in-frame ΔptmR1 dual PTM-PTN overproducing strain. To highlight the potential of this strain for future PTM and PTN biosynthetic studies, we created the ΔptmR1 ΔptmO4 double mutant S. platensis SB12030. Fourteen PTM and PTN congeners, ten of which were new, were isolated from SB12030, shedding new insights into PTM and PTN biosynthesis. PtmO4, a long-chain acyl-CoA dehydrogenase, is strongly implicated to catalyze β-oxidation of the diterpenoid intermediates into the PTM and PTN scaffolds. SB12029 sets the stage for future biosynthetic and bioengineering studies of the PTM and PTN family of natural products. Topics: Acyl-CoA Dehydrogenase, Long-Chain; Adamantane; Aminobenzoates; Aminophenols; Anilides; Bacterial Proteins; Biosynthetic Pathways; Multigene Family; Mutation; Polycyclic Compounds; Streptomyces | 2015 |
Mechanisms of self-resistance in the platensimycin- and platencin-producing Streptomyces platensis MA7327 and MA7339 strains.
Platensimycin (PTM) and platencin (PTN) are potent inhibitors of bacterial fatty acid synthases and have emerged as promising antibacterial drug leads. We previously characterized the PTM and PTN biosynthetic machineries in the Streptomyces platensis producers. We now identify two mechanisms for PTM and PTN resistance in the S. platensis producers-the ptmP3 or ptnP3 gene within the PTM-PTN or PTN biosynthetic cluster and the fabF gene within the fatty acid synthase locus. PtmP3/PtnP3 and FabF confer PTM and PTN resistance by target replacement and target modification, respectively. PtmP3/PtnP3 also represents an unprecedented mechanism for fatty acid biosynthesis in which FabH and FabF are functionally replaced by a single condensing enzyme. These findings challenge the current paradigm for fatty acid biosynthesis and should be considered in future development of effective therapeutics targeting fatty acid synthase. Topics: Adamantane; Amino Acid Substitution; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; Drug Resistance, Bacterial; Fatty Acid Synthase, Type II; Microbial Sensitivity Tests; Molecular Sequence Data; Multigene Family; Polycyclic Compounds; Streptomyces | 2014 |
Strain prioritization for natural product discovery by a high-throughput real-time PCR method.
Natural products offer unmatched chemical and structural diversity compared to other small-molecule libraries, but traditional natural product discovery programs are not sustainable, demanding too much time, effort, and resources. Here we report a strain prioritization method for natural product discovery. Central to the method is the application of real-time PCR, targeting genes characteristic to the biosynthetic machinery of natural products with distinct scaffolds in a high-throughput format. The practicality and effectiveness of the method were showcased by prioritizing 1911 actinomycete strains for diterpenoid discovery. A total of 488 potential diterpenoid producers were identified, among which six were confirmed as platensimycin and platencin dual producers and one as a viguiepinol and oxaloterpin producer. While the method as described is most appropriate to prioritize strains for discovering specific natural products, variations of this method should be applicable to the discovery of other classes of natural products. Applications of genome sequencing and genome mining to the high-priority strains could essentially eliminate the chance elements from traditional discovery programs and fundamentally change how natural products are discovered. Topics: Actinobacteria; Adamantane; Aminobenzoates; Aminophenols; Anilides; Biological Products; Molecular Structure; Polycyclic Compounds; Real-Time Polymerase Chain Reaction; Small Molecule Libraries | 2014 |
Formal syntheses of (±)-platensimycin and (±)-platencin via a dual-mode Lewis acid induced cascade cyclization approach.
A mild and efficient dual-mode Lewis acid induced Diels-Alder (DA)/carbocyclization cascade cyclization reaction has been developed for construction of the tricyclic core of ent-kaurenoids in one pot with the aid of a theoretical study on the π,σ-Lewis acidities of a variety of Lewis acids. With ZnBr2 as the dual-mode Lewis acid, a series of substituted enones and dienes underwent DA/carbocyclization cascade cyclization reaction smoothly at room temperature and provided the tricyclic cyclized products in one pot with good yields and high diastereoselectivity. The tricyclic cyclized product has been successfully utilized as a common intermediate for formal syntheses of (±)-platensimycin and (±)-platencin. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Cyclization; Lewis Acids; Molecular Structure; Polycyclic Compounds; Stereoisomerism | 2013 |
Development of a semi-defined medium supporting production of platensimycin and platencin by Streptomyces platensis.
Platensimycin and platencin are compounds that were discovered at Merck Research Laboratories and have shown promising antibacterial activity. They are both produced in fermentation by the actinomycete Streptomyces platensis. Merck reported a crude, insoluble production medium to produce the antibiotics. To test the possible effects of different primary metabolites and inorganic compounds on the production of these antibiotics, a chemically-defined medium is needed. The effects that these compounds have on production could provide information about the precursors and biosynthetic pathway of the antibiotics. We have tested and developed a number of media with varying degrees of chemical definition and solubility using the Merck medium as our starting point. Our latest production medium, PM5, is soluble and semi-defined. It yields suitable production of the compounds, as shown by agar diffusion assays, bioautography and HPLC. The antibiotics were located in the extracellular broths and not in the mycelia. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Culture Media; Fermentation; Polycyclic Compounds; Streptomyces | 2013 |
Platensimycin and platencin biosynthesis in Streptomyces platensis, showcasing discovery and characterization of novel bacterial diterpene synthases.
Diterpenoid natural products cover a vast chemical diversity and include many medicinally and industrially relevant compounds. All diterpenoids derive from a common substrate, (E,E,E)-geranylgeranyl diphosphate, which is cyclized into one of many scaffolds by a diterpene synthase (DTS). While diterpene biosynthesis has been extensively studied in plants and fungi, bacteria are now recognized for their production of unique diterpenoids and are likely to harbor an underexplored reservoir of new DTSs. Bacterial diterpenoid biosynthesis can be exploited for the discovery of new natural products, a better mechanistic understanding of DTSs, and the rational engineering of whole metabolic pathways. This chapter describes methods and protocols for identification and characterization of bacterial DTSs, based on our recent work with the DTSs involved in platensimycin and platencin biosynthesis. Topics: Adamantane; Alkyl and Aryl Transferases; Aminobenzoates; Aminophenols; Anilides; Bacterial Proteins; Biosynthetic Pathways; Blotting, Southern; Computational Biology; Diterpenes; Electrophoresis, Polyacrylamide Gel; Fermentation; Gene Expression Regulation, Bacterial; Genes, Bacterial; Multigene Family; Mutagenesis; Polycyclic Compounds; Polyisoprenyl Phosphates; Streptomyces | 2012 |
Expression of the platencin biosynthetic gene cluster in heterologous hosts yielding new platencin congeners.
Platensimycin (PTM) and platencin (PTN) are potent and selective inhibitors of bacterial and mammalian fatty acid synthases and have emerged as promising drug leads for both antibacterial and antidiabetic therapies. We have previously cloned and sequenced the PTM-PTN dual biosynthetic gene cluster from Streptomyces platensis MA7327 and the PTN biosynthetic gene cluster from S. platensis MA7339, the latter of which is composed of 31 genes encoding PTN biosynthesis, regulation, and resistance. We have also demonstrated that PTM or PTN production can be significantly improved upon inactivation of the pathway-specific regulator ptmR1 or ptnR1 in S. platensis MA7327 or MA7339, respectively. We now report engineered production of PTN and congeners in a heterologous Streptomyces host. Expression constructs containing the ptn biosynthetic gene cluster were engineered from SuperCos 1 library clones and introduced into five model Streptomyces hosts, and PTN production was achieved in Streptomyces lividans K4-114. Inactivation of ptnR1 was crucial for expression of the ptn biosynthetic gene cluster, thereby PTN production, in S. lividans K4-114. Six PTN congeners, five of which were new, were also isolated from the recombinant strain S. lividans SB12606, revealing new insights into PTN biosynthesis. Production of PTN in a model Streptomyces host provides new opportunities to apply combinatorial biosynthetic strategies to the PTN biosynthetic machinery for structural diversity. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Models, Biological; Multigene Family; Nuclear Magnetic Resonance, Biomolecular; Polycyclic Compounds; Stereoisomerism; Streptomyces | 2012 |
Platensimycin and platencin congeners from Streptomyces platensis.
Platensimycin (1a) and platencin (2) are inhibitors of FabF and FabF/H bacterial fatty acid synthase. The discovery of natural congeners is an approach that can render a better understanding of the structure-function relationships of complex natural products. The isolation and structure elucidation of nine new congeners (11-20) of platensimycin and platencin are described from a fermentation broth of Streptomyces platensis. These hydroxylated congeners are likely derived by cytochrome P450 oxidation of the terpenoid units post-cyclization. Polar groups in the terpenoid portion of the molecule produce negative interactions with the hydrophobic pocket of FabF, resulting in poor activities. However, the discovery of these compounds serves an important purpose, not only to understand structure-function relationships, which cannot be easily accessed by chemical modification, but also to provide access to compounds that could be used for structural identification/confirmation of the oxidative trace metabolites produced in vivo during animal experiments. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Cytochrome P-450 Enzyme System; Fatty Acid Synthase, Type II; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Structure; Polycyclic Compounds; Stereoisomerism; Streptomyces; Structure-Activity Relationship | 2011 |
Dialkylamino-2,4-dihydroxybenzoic acids as easily synthesized analogues of platensimycin and platencin with comparable antibacterial properties.
Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Biological Products; Fatty Acid Synthases; Molecular Structure; Polycyclic Compounds | 2011 |
Proteomic signature of fatty acid biosynthesis inhibition available for in vivo mechanism-of-action studies.
Fatty acid biosynthesis is a promising novel antibiotic target. Two inhibitors of fatty acid biosynthesis, platencin and platensimycin, were recently discovered and their molecular targets identified. Numerous structure-activity relationship studies for both platencin and platensimycin are currently being undertaken. We established a proteomic signature for fatty acid biosynthesis inhibition in Bacillus subtilis using platencin, platensimycin, cerulenin, and triclosan. The induced proteins, FabHA, FabHB, FabF, FabI, PlsX, and PanB, are enzymes involved in fatty acid biosynthesis and thus linked directly to the target pathway. The proteomic signature can now be used to assess the in vivo mechanisms of action of compounds derived from structure-activity relationship programs, as demonstrated for the platensimycin-inspired chromium bioorganometallic PM47. It will further serve as a reference signature for structurally novel natural and synthetic antimicrobial compounds with unknown mechanisms of action. In summary, we described a proteomic signature in B. subtilis consisting of six upregulated proteins that is diagnostic of fatty acid biosynthesis inhibition and thus can be applied to advance antibacterial drug discovery programs. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Bacillus subtilis; Bacterial Proteins; Drug Discovery; Fatty Acids; Polycyclic Compounds; Proteomics | 2011 |
Dedicated ent-kaurene and ent-atiserene synthases for platensimycin and platencin biosynthesis.
Platensimycin (PTM) and platencin (PTN) are potent and selective inhibitors of bacterial and mammalian fatty acid synthases and have emerged as promising drug leads for both antibacterial and antidiabetic therapies. Comparative analysis of the PTM and PTN biosynthetic machineries in Streptomyces platensis MA7327 and MA7339 revealed that the divergence of PTM and PTN biosynthesis is controlled by dedicated ent-kaurene and ent-atiserene synthases, the latter of which represents a new pathway for diterpenoid biosynthesis. The PTM and PTN biosynthetic machineries provide a rare glimpse at how secondary metabolic pathway evolution increases natural product structural diversity and support the wisdom of applying combinatorial biosynthesis methods for the generation of novel PTM and/or PTN analogues, thereby facilitating drug development efforts based on these privileged natural product scaffolds. Topics: Adamantane; Alkyl and Aryl Transferases; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Hypoglycemic Agents; Metabolic Networks and Pathways; Molecular Sequence Data; Polycyclic Compounds; Streptomyces | 2011 |
Engineered Streptomyces platensis strains that overproduce antibiotics platensimycin and platencin.
Platensimycin, which is isolated from Streptomyces platensis MA7327, and platencin, which is isolated from S. platensis MA7339, are two recently discovered natural products that serve as important antibiotic leads. Here we report on the identification of S. platensis MA7327 as a dual producer of both platensimycin and platencin. A PCR-based approach was used to locate and clone the locus involved in platensimycin and platencin production, including ptmR1, which encodes a putative GntR-like transcriptional regulator. Deletion of this gene from the producing organism allowed us to isolate strains that overproduce platensimycin and platencin with yields of 323 +/- 29 mg/liter and 255 +/- 30 mg/liter, respectively. These results illustrate the effectiveness of genetic manipulation for the rational engineering of improvements in titers. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Fermentation; Genetic Engineering; Hydro-Lyases; Multigene Family; Polycyclic Compounds; Polymerase Chain Reaction; Streptomyces | 2009 |
Isolation, enzyme-bound structure and antibacterial activity of platencin A1 from Streptomyces platensis.
Natural products continue to serve as one of the best sources for discovery of antibacterial agents as exemplified by the recent discoveries of platensimycin and platencin. Chemical modifications as well as discovery of congeners are the main sources for gaining knowledge of structure-activity relationship of natural products. Screening for congeners in the extracts of the fermentation broths of Streptomyces platensis led to the isolation of platencin A(1), a hydroxy congener of platencin. The hydroxylation of the tricyclic enone moiety negatively affected the antibacterial activity and appears to be consistent with the hydrophobic binding pocket of the FabF. Isolation, structure, enzyme-bound structure and activity of platencin A(1) and two other congeners have been described. Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Crystallography, X-Ray; Molecular Conformation; Polycyclic Compounds; Streptomyces; Structure-Activity Relationship | 2009 |
High-pressure entry into platencin.
Topics: Adamantane; Aminobenzoates; Aminophenols; Anilides; Anti-Bacterial Agents; Crystallography, X-Ray; Molecular Structure; Polycyclic Compounds; Pressure; Stereoisomerism | 2008 |
Structure and semisynthesis of platensimide A, produced by Streptomyces platensis.
Platensimycin and platencin are novel natural product antibiotics that inhibit bacterial growth by inhibiting condensing enzymes FabF and FabF/FabH of fatty acid biosynthesis pathways, respectively. Continued search for the natural congeners of these compounds led to the isolation of platensic acid, the free C-17 tetracyclic enoic acid, and platensimide A, a 2,4-diaminobutyric acid amide derivative. Isolation, structure, semisynthesis, and activity of these compounds are described. Topics: Adamantane; Aminobenzoates; Aminobutyrates; Aminophenols; Anilides; Anti-Bacterial Agents; Bacteria; Bridged-Ring Compounds; Microbial Sensitivity Tests; Molecular Structure; Polycyclic Compounds; Streptomyces | 2008 |