Nargenicin Explained

Nargenicin (CP-47,444, CS-682) is a 28 carbon macrolide with a fused tricyclic core that has in addition a unique ether bridge. The polyketide antibiotic was isolated from Nocardia argentinensis.^[1] Nargenicin is effective towards gram-positive bacteria and been shown to have strong antibacterial activity against Staphylococcus aureus, including strains that are resistant to methicillin.^[2] It has also been shown to induce cell differentiation and inhibit cell proliferation in a human myeloid leukemia cell line.^[3] __TOC__

Biosynthesis

The biosynthesis of nargenicin is believed to be closely related to fatty acid biosynthesis to produce a polyketide chain. David E. Cane and colleagues have used feeding experiments to determine that nargenicin is derived from common precursors acetate and propionate.^{[4] [5] [6]}

The polyketide chain produced then undergoes a ring closure to form the large lactone ring and a Diels–Alder reaction to form the fused cyclohexane/cyclohexene rings. The oxygen atoms attached to carbons in positions that do not correspond to polyketides—carbons 8 and 13 (the ether bridge), carbon 2 (the methoxy substituent), and carbon 18 (on the hydroxyethyl chain attached to the lactone ring) are derived from molecular oxygen.^[7]

Notes and References

1. Celmer WD, Chmurny GN, Moppett CE, Ware RS, Watts PT, Whipple EB . Structure of natural antibiotic CP-47,444 . J. Am. Chem. Soc. . 1980 . 102 . 12 . 4203–4209 . 10.1021/ja00532a036.
2. Sohng JK, Yamaguchi T, Seong CN, Baik KS, Park SC, Lee HJ, Jang SY, Simkhada JR, Yoo JC . 20377463 . 6 . Production, isolation and biological activity of nargenicin from Nocardia sp. CS682 . Archives of Pharmacal Research . 31 . 10 . 1339–45 . October 2008 . 18958426 . 10.1007/s12272-001-2115-0 .
3. Kim SH, Yoo JC, Kim TS . Nargenicin enhances 1,25-dihydroxyvitamin D(3)- and all-trans retinoic acid-induced leukemia cell differentiation via PKCbetaI/MAPK pathways . Biochemical Pharmacology . 77 . 11 . 1694–701 . June 2009 . 19428323 . 10.1016/j.bcp.2009.03.004 .
4. Cane DE, Yang CC . 10.1021/ja00315a052 . Biosynthetic Origin of the Carbon Skeleton and Oxygen Atoms of Nargenicin A₁ . J. Am. Chem. Soc. . 1984 . 106 . 784–787 . 3.
5. Cane DE, Prabhakaran PC, Tan W, Ott WR . 10.1016/0040-4039(91)80057-D . Macrolide Biosynthesis. 6 Mechanism of Polyketide Chain Elongation . Tetrahedron Lett. . 1991 . 32 . 5457–5460 . 40.
6. Cane DE, Tan W, Ott WR . 10.1021/ja00055a024 . Nargenicin Biosynthesis. Incorporation of Polyketide Chain Elongation Intermediates and Support for a Proposed Intramolecular Diels-Alder Cyclization . J. Am. Chem. Soc. . 1993 . 115 . 527–535 . 2.
7. Cane DE, Yang CC . Nargenicin biosynthesis: late stage oxidations and absolute configuration . The Journal of Antibiotics . 38 . 3 . 423–6 . March 1985 . 4008333 . 10.7164/antibiotics.38.423 . free .