Platensimycin

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Platensimycin
Names
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
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
DrugBank
UNII
  • 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 checkY
    Key: CSOMAHTTWTVBFL-OFBLZTNGSA-N checkY
  • InChI=1/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
    Key: CSOMAHTTWTVBFL-OFBLZTNGBM
  • O=C(O)c1c(O)c(c(O)cc1)NC(=O)CC[C@@]5(C(=O)\C=C/[C@@]34C[C@@]2(O[C@@H](C[C@@H]2C3)[C@H]45)C)C
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).
☒N verify (what is checkY☒N ?)

Platensimycin, a

II (FabF/B)).[1]

History

Platensimycin was first isolated from a strain of Streptomyces platensis by workers at

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

lipophilic tetracyclic ketolide.[4]

Clinical use

Platensimycin is an

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

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.

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.

Mechanism of action

Platensimycin has shown good activity against a panel of Gram-positive bacteria, including various resistant strains.

Platensimycin works by inhibiting beta-ketoacyl syntheses I/II (FabF/B), which are involved in the production of fatty acids required for bacterial cell membranes. It interferes with enzymes involved in the

cell membranes. Other enzymes in this pathway have similarly been proven as antibiotic targets, such as FabI, the enoyl-ACP (acyl carrier protein) reductase, which is inhibited by isoniazid and related compounds and the antiseptic agent triclosan.[13]

One proposed mechanism of action is that, firstly, the

amides
of Cys163 and Phe400.

The

malonyl moiety. In particular, His303 activates a structured water to attack the carboxylate of the incoming malonyl-ACP.[15] The crystal structure of FabF also demonstrates that His340 forms a hydrogen bond between the amide nitrogen of Leu342 and the N-delta- atom of the imidazole
ring meaning that the lone pair must reside on this atom. In the platensimycin crystal structure the structured water adjacent to His303 is no longer present which may suggest an alternative electronic state for this residue. A strong possibility exists that His303 would present itself as a cation capable of forming an ionic interaction with the benzoic acid group of platensimycin.

References

  1. PMID 27865713
    .
  2. S2CID 4329677
    . Retrieved 17 May 2020.
  3. ^ Manallack, David T.; Crosby, I. T.; Khakham, Y; Capuano, B (2008). "Platensimycin: A Promising Antimicrobial Targeting Fatty Acid Synthesis". Current Medicinal Chemistry. 15 (7): 705–10.
    PMID 18336284
    . Retrieved 17 May 2020.
  4. PMID 17013803
    .
  5. PMID 18034483
    .
  6. PMID 19164156
    .
  7. S2CID 3002538
    .
  8. PMID 20158476
    .
  9. ^ S W. White, J. Zheng, Y X M. Zhang, and C O. Rock, Annu. Rev. Biochem. 2005, 74, 791-831.
  10. ^ S. Smith, A. Witkowski, and A K. Joshi, Prog. Lipid Res. 2003, 42, 289-317.
  11. ^ W P. Revill, M J. Bibb, A K. Scheu, H J. Kieser, and D A. Hopwood, J. Bacteriol., 2001, 183, 3526-30.
  12. ^ Häbich, Dieter; von Nussbaum, Franz (2006). "Platensimycin, a New Antibiotic and "Superbug Challenger" from Nature". ChemMedChem. 1 (9): 951–4.
    PMID 16952137
    .
  13. PMID 17707686
    .
  14. ^ A C. Price, C O. Rock, S W. White, J. Bacteriol., 2003, 185, 4136-43.
  15. ^ Y M. Zhang, J. Hurlbert, S W. White, C O. Rock, J. Biol. Chem. 2006, 281, 17390-99.

External links

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