Platensimycin
From Wikipedia, the free encyclopedia
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| IUPAC name
3-[[3-[(1R,3R,4R,5aR,9R,9aS)-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-dihydroxy-benzoic acid | |
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| Properties | |
| C24H27NO7 | |
| Molar mass | 441.480 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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).[1]
Platensimycin was first isolated from a strain of Streptomyces platensis by workers at Merck.[2][3] Screens of 250,000 natural product extracts (83,000 strains in three growth conditions) led to the identification of a potent and selective small molecule from a strain of Streptomyces platensis recovered from a soil sample collected in South Africa. The identification process was carried out using a two-plate system in which control organisms were compared to cells expressing FabF antisense RNA. This method uses a combination of target-based whole-cell and biochemical assays, allowing compounds to be detected at concentrations that would be too low to detect using whole cell assays. The molecule they identified, platensimycin (C24H27NO7, relative molecular mass 441.47), comprises two distinct structural elements connected by an amide bond. The Merck Group showed that platensimycin has potent, broad-spectrum Gram-positive activity in vitro and exhibits no cross-resistance to other key antibiotic-resistant bacteria including Methicillin-resistant Staphylococcus aureus(MRSA), vancomycin-intermediate S. aureus, vancomycin-resistant Enterococci, and linezolid-resistant and macrolide-resistant pathogens.
As confirmed by total synthesis of racemic platensimycin, its structure consists of a 3-amino-2,4-dihydroxybenzoic acid polar part linked through an amide bond to a lipophilic tetracyclic ketolide.[4]
Clinical use
Platensimycin is an experimental drug in preclinical trials involving MRSA in a mouse model. Platensimycin is an effective antibiotic in vivo when continuously administered to cells. Efficacy is reduced when administered by more conventional means.[5] Clinical trials have been delayed.[6] A variety of modifications have been investigated.[7][8] and increase the activity of platensimycin.
Biosynthesis
Biosynthesitic studies show that the benzoic ring is produced from pyruvate and acetate via the TCA cycle, while the C-17 tetracyclic enone acid core is produced from the non-mevalonate terpenoid pathway.
The tetracyclic enone isotope labeling pattern observed is consistent with the biosynthesis of the tetracycle via the non-mevalonate terpenoid pathway.[9][10] This pathway involves condensation of a thiamine-activated acetyl group arising from the decarboxylation of pyruvate and glyceraldehyde-3-phosphate followed by a transposition step. Since both pyruvate and glyceraldehyde-3-phosphate (also glycerol) are part of the glycolytic pathway, varying levels of incorporation are expected. Thus, the terpenoid building blocks, dimethylallyl diphosphate and isopentenyl diphosphate, synthesized by the non-mevalonate pathway utilizing pyruvate and glyceraldehyde-3-phosphate, condense to form the diterpenoid precursor geranylgeranyl diphosphate that cyclizes to an intermediate which is related to (or derived from) ent-kaurene.[11] Oxidative cleavage of the double bond of this intermediate would result in the loss of the terminal three carbons producing the C-17 tetracyclic enone acid unit. An N-acyltransferase reaction of tetracyclic enone and aminobenzoic acid would lead to platensimycin.