Ramoplanin Explained

Ramoplanin (INN) is a glycolipodepsipeptide antibiotic drug derived from strain ATCC 33076 of Actinoplanes.^[1] It is effective against Gram-positive bacteria.

Mechanism

It exerts its bacteriocidal effect by inhibiting cell wall biosynthesis, acting by inhibiting the transglycosylation step of peptidoglycan synthesis.^[2] Ramoplanin specifically binds to and sequesters lipid intermediates I and II, preventing intracellular glycosyltransferase (MurG) and other steps of the peptidoglycan assembly system.^[3]

Uses

Its development has been fast-tracked by the U.S. Food and Drug Administration as a treatment for multiple antibiotic-resistant Clostridium difficile infection of the gastrointestinal tract,^[4] Unlike vancomycin, it is absorbed in the gastrointestinal tract, although it is unstable in the bloodstream, so can be taken only orally against Clostridium difficile infections of the gastrointestinal tract.^{[5] [6] [7]}

Ramoplanin is "particularly useful" in cases E. faecalis no matter its sensitivity to vancomycin.

Chemistry

Ramoplanin is a mixture of three related compounds that vary in the acyl group on the Asn N-terminus, with the most abundant form (shown in the infobox) being A2.^[3]

Synthesis

Biosynthesis

The biosynthesis is performed by a 33-gene cluster containing nonribosomal peptide synthetase genes and supporting enzymes for amino acid and fatty acid synthesis, revealed by sequencing of the producer strain in 2002. Initial investigation into the functions of individual genes was conducted in 2012.^[8]

Total synthesis

The general synthesis of Ramoplanin A1, A2 and A3 aglycons entails the preparation of residues 3-9 (heptapeptide 15), pentadepsipeptide 26 (residues 1, 2 and 15–17) along with pentapeptide 34 (residues 10–14), subsequent coupling, and cyclization to create the 49-membered aglycon core of the compound.^[9] The synthesis of Ramoplanin A2 aglycon and A3 aglycon are very similar to scheme 6, where ramoplanin A1 aglycon requires the corresponding acyl group and DMF, while ramoplanin A3 aglycon synthesis requires both , i-PrOH, and then treatment with the acyl group and DMF.^[3]

Notes and References

1. Farver DK, Hedge DD, Lee SC . Ramoplanin: a lipoglycodepsipeptide antibiotic . The Annals of Pharmacotherapy . 39 . 5 . 863–868 . May 2005 . 15784805 . 10.1345/aph.1E397 . 6026698 .
2. Fang X, Tiyanont K, Zhang Y, Wanner J, Boger D, Walker S . The mechanism of action of ramoplanin and enduracidin . Molecular BioSystems . 2 . 1 . 69–76 . January 2006 . 16880924 . 10.1039/b515328j .
3. Shin D, Rew Y, Boger DL . Total synthesis and structure of the ramoplanin A1 and A3 aglycons: two minor components of the ramoplanin complex . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 11977–11979 . August 2004 . 15175429 . 514419 . 10.1073/pnas.0401419101 . free .
4. Fulco P, Wenzel RP . Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent . Expert Review of Anti-Infective Therapy . 4 . 6 . 939–945 . December 2006 . 17181409 . 10.1586/14787210.4.6.939 . 12881565 .
5. Scheinfeld N . A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and enterococcus . Journal of Drugs in Dermatology . 6 . 1 . 97–103 . January 2007 . 17373167 .
6. Balagopal A, Sears CL . Clostridium difficile: new therapeutic options . Current Opinion in Pharmacology . 7 . 5 . 455–458 . October 2007 . 17644040 . 10.1016/j.coph.2007.05.007 .
7. Gerding DN, Muto CA, Owens RC . Treatment of Clostridium difficile infection . Clinical Infectious Diseases . 46 . S32–S42 . January 2008 . Suppl 1 . 18177219 . 10.1086/521860 . free .
8. Hoertz AJ, Hamburger JB, Gooden DM, Bednar MM, McCafferty DG . Studies on the biosynthesis of the lipodepsipeptide antibiotic Ramoplanin A2 . Bioorganic & Medicinal Chemistry . 20 . 2 . 859–865 . January 2012 . 22222159 . 10.1016/j.bmc.2011.11.062 .
9. Jiang W, Wanner J, Lee RJ, Bounaud PY, Boger DL . Total synthesis of the ramoplanin A2 and ramoplanose aglycon . Journal of the American Chemical Society . 125 . 7 . 1877–1887 . February 2003 . 12580615 . 10.1021/ja0212314 .