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| platensimycin |
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| CHEBI:68236 |
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| A monocarboxylic acid amide obtained by the formal condensation of the amino group of 3-amino-2,4-dihydroxybenzoic acid with the carboxy group of the oxatetracyclic cage component. It is an antibiotic isolated from Streptomyces platensis and exhibits inhibitory activity against fatty acid synthase. |
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This entity has been manually annotated by the ChEBI Team.
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| ZINC000029050726 |
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Molfile
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SDF
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more structures >>
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Ideal conformer Mrv1927 09072114183D starting HoverWatcher_5 Time for openFile(PMN - Ideal conformer Mrv1927 09072114183D 59 63 0 0 0 0 999 V2000 3.2550 -1.9130 -1.2630 O 0 0 0 0 0 0 0 0 0 0 0 0 1.5580 2.9950 1.1960 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.7600 0.1530 1.1790 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.7270 2.7090 -1.9290 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.2580 -1.4580 0.3260 O 0 0 0 0 0 0 0 0 0 0 0 0 -5.3540 -2.5850 1.0890 O 0 0 0 0 0 0 0 0 0 0 0 0 -7.3940 -1.7630 0.7810 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.0800 0.7080 -0.9460 N 0 0 0 0 0 0 0 0 0 0 0 0 -1.2810 0.5040 0.1210 C 0 0 0 0 0 0 0 0 0 0 0 0 0.2060 0.7130 -0.0010 C 0 0 1 0 0 0 0 0 0 0 0 0 0.8750 0.4170 1.3430 C 0 0 1 0 0 0 0 0 0 0 0 0 2.3730 0.7630 1.2580 C 0 0 2 0 0 0 0 0 0 0 0 0 2.4910 2.2540 0.9730 C 0 0 0 0 0 0 0 0 0 0 0 0 3.7470 2.7680 0.4260 C 0 0 0 0 0 0 0 0 0 0 0 0 4.6380 1.9460 -0.1280 C 0 0 0 0 0 0 0 0 0 0 0 0 4.4240 0.4840 -0.2240 C 0 0 2 0 0 0 0 0 0 0 0 0 3.0080 0.0320 0.0970 C 0 0 1 0 0 0 0 0 0 0 0 0 2.8570 -1.4820 0.0770 C 0 0 2 0 0 0 0 0 0 0 0 0 3.9570 -2.1780 0.9160 C 0 0 1 0 0 0 0 0 0 0 0 0 5.2190 -1.7550 0.1020 C 0 0 2 0 0 0 0 0 0 0 0 0 5.4770 -0.2980 0.5920 C 0 0 1 0 0 0 0 0 0 0 0 0 4.7250 -0.0700 -1.6460 C 0 0 1 0 0 0 0 0 0 0 0 0 4.6690 -1.5980 -1.3480 C 0 0 2 0 0 0 0 0 0 0 0 0 5.4200 -2.4480 -2.3750 C 0 0 0 0 0 0 0 0 0 0 0 0 3.0230 0.4600 2.6050 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.0540 -1.6940 0.6500 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.4390 -0.5410 -0.0260 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.0450 -0.4670 -0.1640 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.4740 0.6260 -0.8040 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.2860 1.6410 -1.3040 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.6670 1.5640 -1.1650 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.2440 0.4840 -0.5380 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.5500 2.5660 -2.8680 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.0840 -2.1700 -0.3060 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.7520 -2.5400 1.2320 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.6910 0.9110 -1.8110 H 0 0 0 0 0 0 0 0 0 0 0 0 0.6060 0.0420 -0.7620 H 0 0 0 0 0 0 0 0 0 0 0 0 0.4060 1.7460 -0.2870 H 0 0 0 0 0 0 0 0 0 0 0 0 0.4070 1.0180 2.1220 H 0 0 0 0 0 0 0 0 0 0 0 0 0.7590 -0.6410 1.5810 H 0 0 0 0 0 0 0 0 0 0 0 0 3.9550 3.8290 0.4720 H 0 0 0 0 0 0 0 0 0 0 0 0 5.5560 2.3640 -0.5240 H 0 0 0 0 0 0 0 0 0 0 0 0 2.4130 0.3670 -0.7970 H 0 0 0 0 0 0 0 0 0 0 0 0 1.8550 -1.8270 0.3220 H 0 0 0 0 0 0 0 0 0 0 0 0 4.0000 -1.8310 1.9410 H 0 0 0 0 0 0 0 0 0 0 0 0 3.8320 -3.2680 0.8940 H 0 0 0 0 0 0 0 0 0 0 0 0 6.0710 -2.4260 0.1960 H 0 0 0 0 0 0 0 0 0 0 0 0 6.4900 0.0220 0.3180 H 0 0 0 0 0 0 0 0 0 0 0 0 5.3390 -0.2040 1.6630 H 0 0 0 0 0 0 0 0 0 0 0 0 3.9500 0.2310 -2.3490 H 0 0 0 0 0 0 0 0 0 0 0 0 5.7130 0.2400 -1.9790 H 0 0 0 0 0 0 0 0 0 0 0 0 5.0020 -2.2740 -3.3660 H 0 0 0 0 0 0 0 0 0 0 0 0 6.4750 -2.1720 -2.3730 H 0 0 0 0 0 0 0 0 0 0 0 0 5.3200 -3.5020 -2.1180 H 0 0 0 0 0 0 0 0 0 0 0 0 2.9000 -0.5980 2.8380 H 0 0 0 0 0 0 0 0 0 0 0 0 4.0850 0.7010 2.5590 H 0 0 0 0 0 0 0 0 0 0 0 0 2.5480 1.0610 3.3810 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.2910 2.3550 -1.5560 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.3170 0.4280 -0.4370 H 0 0 0 0 0 0 0 0 0 0 0 0 1 18 1 0 0 0 0 1 23 1 0 0 0 0 2 13 2 0 0 0 0 3 9 2 0 0 0 0 4 30 1 0 0 0 0 4 33 1 0 0 0 0 5 28 1 0 0 0 0 5 34 1 0 0 0 0 6 26 2 0 0 0 0 7 26 1 0 0 0 0 7 35 1 0 0 0 0 8 9 1 0 0 0 0 8 29 1 0 0 0 0 8 36 1 0 0 0 0 9 10 1 0 0 0 0 10 11 1 0 0 0 0 10 37 1 0 0 0 0 10 38 1 0 0 0 0 12 11 1 1 0 0 0 11 39 1 0 0 0 0 11 40 1 0 0 0 0 12 13 1 0 0 0 0 12 17 1 0 0 0 0 12 25 1 0 0 0 0 13 14 1 0 0 0 0 14 15 2 0 0 0 0 14 41 1 0 0 0 0 16 15 1 6 0 0 0 15 42 1 0 0 0 0 16 17 1 0 0 0 0 16 21 1 0 0 0 0 16 22 1 0 0 0 0 17 18 1 0 0 0 0 17 43 1 6 0 0 0 18 19 1 0 0 0 0 18 44 1 1 0 0 0 19 20 1 0 0 0 0 19 45 1 0 0 0 0 19 46 1 0 0 0 0 20 21 1 0 0 0 0 20 23 1 0 0 0 0 20 47 1 6 0 0 0 21 48 1 0 0 0 0 21 49 1 0 0 0 0 22 23 1 0 0 0 0 22 50 1 0 0 0 0 22 51 1 0 0 0 0 23 24 1 6 0 0 0 24 52 1 0 0 0 0 24 53 1 0 0 0 0 24 54 1 0 0 0 0 25 55 1 0 0 0 0 25 56 1 0 0 0 0 25 57 1 0 0 0 0 26 27 1 0 0 0 0 27 28 2 0 0 0 0 27 32 1 0 0 0 0 28 29 1 0 0 0 0 29 30 2 0 0 0 0 30 31 1 0 0 0 0 31 32 2 0 0 0 0 31 58 1 0 0 0 0 32 59 1 0 0 0 0 M END): 19 ms reading 59 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. 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| Platensimycin, a metabolite of Streptomyces platensis, is an antibiotic, which acts by blocking the enzymes β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B). |
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Read full article at Wikipedia
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InChI=1S/C24H27NO7/c1- 22(7-6-17(28)25-18-14(26)4-3-13(19(18)29)21(30)31)16(27)5-8-24-10-12-9-15(20(22)24)32-23(12,2)11-24/h3-5,8,12,15,20,26,29H,6-7,9-11H2,1-2H3,(H,25,28)(H,30,31)/t12-,15+,20+,22-,23+,24+/m1/s1 |
| CSOMAHTTWTVBFL-OFBLZTNGSA-N |
| [H][C@]12C[C@@H]3O[C@@]1(C)C[C@@]1(C2)C=CC(=O)[C@@](C)(CCC(=O)NC2=C(O)C(=CC=C2O)C(O)=O)[C@]31[H] |
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Streptomyces platensis
(NCBI:txid58346)
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of strain
MA7327
See:
PubMed
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Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
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bacterial metabolite
Any prokaryotic metabolite produced during a metabolic reaction in bacteria.
antimicrobial agent
A substance that kills or slows the growth of microorganisms, including bacteria, viruses, fungi and protozoans.
EC 2.3.1.85 (fatty acid synthase) inhibitor
An EC 2.3.1.* (acyltransferase transferring other than amino-acyl group) inhibitor that interferes with the action of fatty acid synthase (EC 2.3.1.85), a multi-enzyme protein involved in fatty acid synthesis.
antibacterial agent
A substance (or active part thereof) that kills or slows the growth of bacteria.
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View more via ChEBI Ontology
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3-({3-[(1S,4aS,6S,7S,9S,9aR)-1,6-dimethyl-2-oxo-1,2,5,6,7,8,9,9a-octahydro-6,9-epoxy-4a,7-methanobenzo[7]annulen-1-yl]propanoyl}amino)-2,4-dihydroxybenzoic acid
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(−)-platensimycin
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KEGG COMPOUND
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3-[[3-[(1S,3S,4S,5aS,9S,9aR)-1,4,5,8,9,9a-Hexahydro-3,9-dimethyl-8-oxo-3H-1,4:3,5a-dimethano-2-benzoxepin-9-yl]-1-oxopropyl]amino]-2,4-dihydroxybenzoic acid
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ChemIDplus
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10740321
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Reaxys Registry Number
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Reaxys
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835876-32-9
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CAS Registry Number
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KEGG COMPOUND
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835876-32-9
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CAS Registry Number
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ChemIDplus
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Espeland LO, Georgiou C, Klein R, Bhukya H, Haug BE, Underhaug J, Mainkar PS, Brenk R (2021)
An Experimental Toolbox for Structure-Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics.
ChemMedChem 16, 2715-2726 [PubMed:34189850]
[show Abstract]
FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target for new antibiotics. Here, we focus on FabF from P. aeruginosa (PaFabF) as antibiotics against this pathogen are urgently needed. To facilitate exploration of this target we have set up an experimental toolbox consisting of binding assays using bio-layer interferometry (BLI) as well as saturation transfer difference (STD) and WaterLOGSY NMR in addition to robust conditions for structure determination. The suitability of the toolbox to support structure-based design of FabF inhibitors was demonstrated through the validation of hits obtained from virtual screening. Screening a library of almost 5 million compounds resulted in 6 compounds for which binding into the malonyl-binding site of FabF was shown. For one of the hits, the crystal structure in complex with PaFabF was determined. Based on the obtained binding mode, analogues were designed and synthesised, but affinity could not be improved. This work has laid the foundation for structure-based exploration of PaFabF. | Wang Z, Liu X, Peng Y, Su M, Zhu S, Pan J, Shen B, Duan Y, Huang Y (2020)
Platensimycin-Encapsulated Liposomes or Micelles as Biosafe Nanoantibiotics Exhibited Strong Antibacterial Activities against Methicillin-Resistant Staphylococcus aureus Infection in Mice.
Molecular pharmaceutics 17, 2451-2462 [PubMed:32519867]
[show Abstract]
Platensimycin (PTM) is a promising natural product drug lead against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), while the clinical development was hampered by problems related to its poor solubility and pharmacokinetic properties. In this study, we used liposomes and micelles as carriers of PTM to prepare PTM nanoformulations for the treatment of MRSA infection in mice. PTM-loaded nanoparticles could effectively reduce residual bacteria in the MRSA-infected macrophage cell model, comparing to free PTM. More importantly, in vivo studies showed that encapsulation of PTM by liposomes or micelles effectively improved the pharmacokinetic properties of PTM in Sprague-Dawley rats and the survival rate of MRSA-infected C57BL/6J mice. Our study has thus suggested that the clinically used nanocarriers, such as liposome and micelle, might also be useful to improve the efficacy of other natural product drug leads to accelerate their in vivo evaluation and preclinical development. | Deng Y, Weng X, Li Y, Su M, Wen Z, Ji X, Ren N, Shen B, Duan Y, Huang Y (2019)
Late-Stage Functionalization of Platensimycin Leading to Multiple Analogues with Improved Antibacterial Activity in Vitro and in Vivo.
Journal of medicinal chemistry 62, 6682-6693 [PubMed:31265289]
[show Abstract]
Bacterial fatty acid synthases are promising antibacterial targets against multidrug-resistant pathogens. Platensimycin (PTM) is a potent FabB/FabF inhibitor, while its poor pharmacokinetics hampers the clinical development. In this study, a focused library of PTM derivatives was prepared through thiolysis of PTM oxirane (1), followed by various C-C cross-coupling reactions in high yields. Antibacterial screening of these compounds in vitro yielded multiple hits with improved anti-Staphylococcus activities over PTM. Among them, compounds A1, A3, A17, and A28 exhibited improved antibacterial activities over PTM against methicillin-resistant Staphylococcus aureus (MRSA) in a mouse peritonitis model. Compound A28 was further shown to be effective against MRSA infection in a mouse wound model, in comparison to mupirocin. Therefore, the facile preparation and screening of these PTM derivatives, together with their potent antibacterial activities in vivo, suggest a promising strategy to improve the antibacterial activity and pharmacokinetic properties of PTM. | Dong LB, Zhang X, Rudolf JD, Deng MR, Kalkreuter E, Cepeda AJ, Renata H, Shen B (2019)
Cryptic and Stereospecific Hydroxylation, Oxidation, and Reduction in Platensimycin and Platencin Biosynthesis.
Journal of the American Chemical Society 141, 4043-4050 [PubMed:30735041]
[show Abstract]
Platensimycin (PTM) and platencin (PTN) are highly functionalized bacterial diterpenoids of ent-kauranol and ent-atiserene biosynthetic origin. C7 oxidation in the B-ring plays a key biosynthetic role in generating structural complexity known for ent-kaurane and ent-atisane derived diterpenoids. While all three oxidation patterns, α-hydroxyl, β-hydroxyl, and ketone, at C7 are seen in both the ent-kaurane and ent-atisane derived diterpenoids, their biosynthetic origins remain largely unknown. We previously established that PTM and PTN are produced by a single biosynthetic machinery, featuring cryptic C7 oxidations at the B-rings that transform the ent-kauranol and ent-atiserene derived precursors into the characteristic PTM and PTN scaffolds. Here, we report a three-enzyme cascade affording C7 α-hydroxylation in PTM and PTN biosynthesis. Combining in vitro and in vivo studies, we show that PtmO3 and PtmO6 are two functionally redundant α-ketoglutarate-dependent dioxygenases that generate a cryptic C7 β-hydroxyl on each of the ent-kauranol and ent-atiserene scaffolds, and PtmO8 and PtmO1, a pair of NAD+/NADPH-dependent dehydrogenases, subsequently work in concert to invert the C7 β-hydroxyl to α-hydroxyl via a C7 ketone intermediate. PtmO3 and PtmO6 represent the first dedicated C7 β-hydroxylases characterized to date and, together with PtmO8 and PtmO1, provide an account for the biosynthetic origins of all three C7 oxidation patterns that may shed light on other B-ring modifications in bacterial, plant, and fungal diterpenoid biosynthesis. Given their unprecedented activities in C7 oxidations, PtmO3, PtmO6, PtmO8, and PtmO1 enrich the growing toolbox of novel enzymes that could be exploited as biocatalysts to rapidly access complex diterpenoid natural products. | Dong LB, Liu YC, Cepeda AJ, Kalkreuter E, Deng MR, Rudolf JD, Chang C, Joachimiak A, Phillips GN, Shen B (2019)
Characterization and Crystal Structure of a Nonheme Diiron Monooxygenase Involved in Platensimycin and Platencin Biosynthesis.
Journal of the American Chemical Society 141, 12406-12412 [PubMed:31291107]
[show Abstract]
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. | Qiu L, Wen Z, Li Y, Tian K, Deng Y, Shen B, Duan Y, Huang Y (2019)
Stereoselective functionalization of platensimycin and platencin by sulfa-Michael/aldol reactions.
Organic & biomolecular chemistry 17, 4261-4272 [PubMed:30816397]
[show Abstract]
Bioinspired sulfa-Michael/aldol cascade reactions have been developed for the semisynthesis of sulfur-containing heterocyclic derivatives of platensimycin and platencin, with three newly formed contiguous stereogenic centers. Density functional theory calculations revealed the mechanism for the stereochemistry control. This method was used in a synthesis of a platensimycin thiophene analogue with potent antibacterial activities against Staphylococcus aureus. | Tian K, Deng Y, Qiu L, Zhu X, Shen B, Duan Y, Huang Y (2018)
Semisynthesis and Biological Evaluation of Platensimycin Analogues with Varying Aminobenzoic Acids.
ChemistrySelect 3, 12625-12629 [PubMed:32232122]
[show Abstract]
Platensimycin (PTM) is an excellent natural product drug lead against various gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. In this study, twenty PTM derivatives with varying aminobenzoic acids were semisynthesized. In contrast to all the previous reported inactive aminobenzaote analogues, a few of them showed moderate antibacterial activities against S. aureus. Our study suggested that modification of the conserved aminobenzoic acid remains a viable approach to diversify the PTM scaffold. | Deng Y, Su M, Kang D, Liu X, Wen Z, Li Y, Qiu L, Shen B, Duan Y, Huang Y (2018)
Semisynthesis of Platensimycin Derivatives with Antibiotic Activities in Mice via Suzuki-Miyaura Cross-Coupling Reactions.
Journal of medicinal chemistry 61, 11341-11348 [PubMed:30461269]
[show Abstract]
Platensimycin (PTM), originally isolated from soil bacteria Streptomyces platensis, is a potent FabF inhibitor against many Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. However, the further clinical development of PTM is hampered by its poor pharmacokinetic properties. In this study, 20 PTM derivatives were prepared by Suzuki-Miyaura cross-coupling reactions catalyzed by Pd (0)/C. Compared to PTM, 6-pyrenyl PTM (6t) showed improved antibacterial activity against MRSA in a mouse peritonitis model. Our results support the strategy to target the essential fatty acid synthases in major pathogens, in order to discover and develop new generations of antibiotics. | Rudolf JD, Dong LB, Zhang X, Renata H, Shen B (2018)
Cytochrome P450-Catalyzed Hydroxylation Initiating Ether Formation in Platensimycin Biosynthesis.
Journal of the American Chemical Society 140, 12349-12353 [PubMed:30216060]
[show Abstract]
Platensimycin (PTM) and platencin (PTN) are potent and selective inhibitors of bacterial and mammalian fatty acid synthases. The regio- and stereospecificity of the ether oxygen atom in PTM, which PTN does not have, strongly contribute to the selectivity and potency of PTM. We previously reported the biosynthetic origin of the 11 S,16 S-ether moiety by characterizing the diterpene synthase PtmT3 as a (16 R)- ent-kauran-16-ol synthase and isolating 11-deoxy-16 R-hydroxylated congeners of PTM from the Δ ptmO5 mutant. PtmO5, a cytochrome P450, was proposed to catalyze formation of the ether moiety in PTM. Here we report the in vitro characterization of PtmO5, revealing that PtmO5 stereoselectively hydroxylates the C-11 position of the ent-kaurane scaffold resulting in an 11 S,16 R-diol intermediate. The ether moiety, the oxygen of which originates from the P450-catalyzed hydroxylation at C-11, is formed via cyclization of the diol intermediate. This study provides mechanistic insight into ether formation in natural product biosynthetic pathways. | Shi J, Pan J, Liu L, Yang D, Lu S, Zhu X, Shen B, Duan Y, Huang Y (2016)
Titer improvement and pilot-scale production of platensimycin from Streptomyces platensis SB12026.
Journal of industrial microbiology & biotechnology 43, 1027-1035 [PubMed:27126098]
[show Abstract]
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. | Singh SB, Kang L, Nawrocki AR, Zhou D, Wu M, Previs S, Miller C, Liu H, Hines CD, Madeira M, Cao J, Herath K, Spears LD, Semenkovich, Wang L, Kelley DE, Li C, Guan HP (2016)
The Fatty Acid Synthase Inhibitor Platensimycin Improves Insulin Resistance without Inducing Liver Steatosis in Mice and Monkeys.
PloS one 11, e0164133 [PubMed:27695056]
[show Abstract]
ObjectivesPlatensimycin (PTM) is a natural antibiotic produced by Streptomyces platensis that selectively inhibits bacterial and mammalian fatty acid synthase (FAS) without affecting synthesis of other lipids. Recently, we reported that oral administration of PTM in mouse models (db/db and db/+) with high de novo lipogenesis (DNL) tone inhibited DNL and enhanced glucose oxidation, which in turn led to net reduction of liver triglycerides (TG), reduced ambient glucose, and improved insulin sensitivity. The present study was conducted to explore translatability and the therapeutic potential of FAS inhibition for the treatment of diabetes in humans.MethodsWe tested PTM in animal models with different DNL tones, i.e. intrinsic synthesis rates, which vary among species and are regulated by nutritional and disease states, and confirmed glucose-lowering efficacy of PTM in lean NHPs with quantitation of liver lipid by MRS imaging. To understand the direct effect of PTM on liver metabolism, we performed ex vivo liver perfusion study to compare FAS inhibitor and carnitine palmitoyltransferase 1 (CPT1) inhibitor.ResultsThe efficacy of PTM is generally reproduced in preclinical models with DNL tones comparable to humans, including lean and established diet-induced obese (eDIO) mice as well as non-human primates (NHPs). Similar effects of PTM on DNL reduction were observed in lean and type 2 diabetic rhesus and lean cynomolgus monkeys after acute and chronic treatment of PTM. Mechanistically, PTM lowers plasma glucose in part by enhancing hepatic glucose uptake and glycolysis. Teglicar, a CPT1 inhibitor, has similar effects on glucose uptake and glycolysis. In sharp contrast, Teglicar but not PTM significantly increased hepatic TG production, thus caused liver steatosis in eDIO mice.ConclusionsThese findings demonstrate unique properties of PTM and provide proof-of-concept of FAS inhibition having potential utility for the treatment of diabetes and related metabolic disorders. | Horii S, Torihata M, Nagasawa T, Kuwahara S (2013)
Stereoselective approach to the racemic oxatetracyclic core of platensimycin.
The Journal of organic chemistry 78, 2798-2801 [PubMed:23373732]
[show Abstract]
A highly stereoselective synthesis of the racemic oxatetracyclic core of platensimycin has been accomplished from a known bicyclic epoxy lactone by an 11-step sequence that involves a Diels-Alder cyclcoaddition to construct its cis-decalenone structural motif with complete regio- and stereoselectivity and a ring-closing metathesis to establish its whole carbon framework. | Zhang C, Ondeyka J, Herath K, Jayasuriya H, Guan Z, Zink DL, Dietrich L, Burgess B, Ha SN, Wang J, Singh SB (2011)
Platensimycin and platencin congeners from Streptomyces platensis.
Journal of natural products 74, 329-340 [PubMed:21214253]
[show Abstract]
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. | Saleem M, Hussain H, Hussain H, Ahmed I, van Ree T, Krohn K (2011)
Platensimycin and its relatives: a recent story in the struggle to develop new naturally derived antibiotics.
Natural product reports 28, 1534-1579 [PubMed:21808805] | Martens E, Demain AL (2011)
Platensimycin and platencin: promising antibiotics for future application in human medicine.
The Journal of antibiotics 64, 705-710 [PubMed:21915133]
[show Abstract]
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. | Lu X, You Q (2010)
Recent advances on platensimycin: a potential antimicrobial agent.
Current medicinal chemistry 17, 1139-1155 [PubMed:20158476]
[show Abstract]
Platensimycin, an active metabolite of Streptomyces platensis, was initially discovered by a combination of RNA interferin induced gene-silencing and library screening to microbial extracts. Platensimycin selectively inhibits beta - ketoacyl-acyl carrier protein (ACP) synthase II (FabF) that is recognized as an effective broad-spectrum antibiotic against drug-resistant microorganism strains. Its novel scaffold and extraordinary antibacterial activity have drawn great attentions in recent years. So far, a number of synthetic strategies have been explored for the total synthesis of platensimycin. Moreover, many analogues have been investigated in terms of structure-activity relationships (SAR). This review provides a detailed overview of updated studies on platensimycin, focusing on various total and formal synthetic strategies, development of analogues, and the structure-activity relationships. | Singh SB, Ondeyka JG, Herath KB, Zhang C, Jayasuriya H, Zink DL, Parthasarathy G, Becker JW, Wang J, Soisson SM (2009)
Isolation, enzyme-bound structure and antibacterial activity of platencin A1 from Streptomyces platensis.
Bioorganic & medicinal chemistry letters 19, 4756-4759 [PubMed:19581087]
[show Abstract]
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. | Wang J, Soisson SM, Young K, Shoop W, Kodali S, Galgoci A, Painter R, Parthasarathy G, Tang YS, Cummings R, Ha S, Dorso K, Motyl M, Jayasuriya H, Ondeyka J, Herath K, Zhang C, Hernandez L, Allocco J, Basilio A, Tormo JR, Genilloud O, Vicente F, Pelaez F, Colwell L, Lee SH, Michael B, Felcetto T, Gill C, Silver LL, Hermes JD, Bartizal K, Barrett J, Schmatz D, Becker JW, Cully D, Singh SB (2006)
Platensimycin is a selective FabF inhibitor with potent antibiotic properties.
Nature 441, 358-361 [PubMed:16710421]
[show Abstract]
Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity. |
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