Platensimycin
Encyclopedia
Platensimycin, a metabolite of Streptomyces platensis, which is an excellent example of a unique structural class of natural antibiotics, has been demonstrated to be a breakthrough in recent antibiotic researches due to its unique functional pattern and significant antibacterial activity . This compound is a member of a class of antibiotics which act by blocking enzymes involved in the condensation steps in fatty acid biosynthesis, which Gram-positive bacteria need to biosynthesise cell membranes (β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B)). Other enzymes in this pathway have similarly been proven antibiotic targets for example FabI, the enoyl-ACP (acyl carrier protein) reductase, that is inhibited by isoniazid and related compounds and the antiseptic agent triclosan.
[1]
A first total synthesis of racemic platensimycin has been published.[7] Its structure consists of a 3-amino-2,4-dihydroxybenzoic acid polar part linked through an amide bond to a lipophilic pentacyclicketolide.
Since the importance of platensimycin, it has been studied to improve the production by gene regulation and it is also emphasized recently to investigate the tolerance of modification without affecting activity by chemical modifications , which can hopefully create the easier synthetic pathway or increase the activity of platensimycin.
Singh Group observed tetracyclic enone isotope labeling pattern is consistent with the biosynthesis of the tetracycle via the non-mevalonate terpenoid pathway proposed by Rohmer et al. and Arigoni and co-workers. This pathway involves condensation of a thiamine-activated acetyl group arising from the decarboxylation of pyruvate and glyceraldehye-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 incorporations 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 intermediate 3 which is related to (or derived from) ent-kaurene . Oxidative cleavage of the double bond of 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.
Because of the dissimilarity between plantensimycin's mechanism of action and that of conventional antibiotics, it is believed that the capacity for the development of resistance by bacteria may be substantially decreased.
History
Platensimycin was first isolated from a strain of Streptomyces platensis by the Merck group [1] by using two-plate system where control organisms were compared to cells expressing fabF antisense RNA. This method uses the combination of target-based whole-cell and biochemical assays. The advantage of this method is that the concentrations of compounds in these extracts is sometimes too low to be identified in whole cell assays but are easily found in this two-plate assay system. They tried to find a drug targeting condensing enzymes and can be used clinically. Therefore, they systematically screened 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. This molecule, platensimycin (C24H27NO7, relative molecular mass 441.47), comprises two distinct structural elements connected by an amide bond. They still showed that Platensimycin has potent, broad-spectrum Gram-positive activity in vitro (Table below) and exhibits no cross-resistance to other key antibiotic-resistant bacteria including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus, vancomycin-resistant Enterococci, and linezolid-resistant and macrolide-resistant pathogens.[1]
A first total synthesis of racemic platensimycin has been published.[7] Its structure consists of a 3-amino-2,4-dihydroxybenzoic acid polar part linked through an amide bond to a lipophilic pentacyclicketolide.
Clinical use
Platensimycin is an experimental new drug in preclinical trials in an effort to combat MRSA in a mouse model.[1] Platensimycin is a very effective antibiotic in vivo when continuously administered to cells, however this efficacy is reduced when administered by more conventional means. Consequently, and in light of the elevated levels of the drug necessary for effectiveness, clinical trials have been delayed pending the development of variants of similar chemical form which have more favorable properties.Since the importance of platensimycin, it has been studied to improve the production by gene regulation and it is also emphasized recently to investigate the tolerance of modification without affecting activity by chemical modifications , which can hopefully create the easier synthetic pathway or increase the activity of platensimycin.
Biosynthesis
The biosynthesis of plantensimycin has been studied by Singh Group[6] using isotope incorporation experiments to 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 pathway is shown as below.[6]Singh Group observed tetracyclic enone isotope labeling pattern is consistent with the biosynthesis of the tetracycle via the non-mevalonate terpenoid pathway proposed by Rohmer et al. and Arigoni and co-workers. This pathway involves condensation of a thiamine-activated acetyl group arising from the decarboxylation of pyruvate and glyceraldehye-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 incorporations 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 intermediate 3 which is related to (or derived from) ent-kaurene . Oxidative cleavage of the double bond of 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
Aminobenzoic acid
Aminobenzoic acid can refer to:* para-Aminobenzoic acid * 3-Aminobenzoic acid...
would lead to platensimycin.
Because of the dissimilarity between plantensimycin's mechanism of action and that of conventional antibiotics, it is believed that the capacity for the development of resistance by bacteria may be substantially decreased.