Ramoplanin

Medical uses

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

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

Mechanism of action

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

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.

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.

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. 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. File:Remoplanin Synthesis 1 - Synthesis of Hpg3-Phe9 Subunit.png|1 - Synthesis of Hpg3-Phe9 Subunit File:Ramoplanin Synthesis 2 - Fmoc-L-HAsn(Trt)-Obn Preparation.png|2 - Fmoc-L-HAsn(Trt)-Obn Preparation File:Ramoplanin Synthesis 3 - Synthesis of Depsipeptide subunit.png|3 - Synthesis of Depsipeptide subunit File:Ramoplanin Scheme 4 - Synthesis of Orn10-Gly14 Subunit.png|4 - Synthesis of Orn10-Gly14 Subunit File:Ramoplanin Synthesis 6 - Preparation of acyl group.png|5 - Preparation of acyl group File:Ramoplanin Synthesis 7 - Deprotection.png|6 - Deprotection

References

References

1. (May 2005). "Ramoplanin: a lipoglycodepsipeptide antibiotic". The Annals of Pharmacotherapy.
2. (December 2006). "Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent". Expert Review of Anti-Infective Therapy.
3. (January 2007). "A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and enterococcus". Journal of Drugs in Dermatology.
4. (October 2007). "Clostridium difficile: new therapeutic options". Current Opinion in Pharmacology.
5. (January 2008). "Treatment of Clostridium difficile infection". Clinical Infectious Diseases.
6. (2007-01-01). "Comprehensive Medicinal Chemistry". Elsevier.
7. (January 2006). "The mechanism of action of ramoplanin and enduracidin". Molecular BioSystems.
8. (August 2004). "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.
9. (January 2012). "Studies on the biosynthesis of the lipodepsipeptide antibiotic Ramoplanin A2". Bioorganic & Medicinal Chemistry.
10. (February 2003). "Total synthesis of the ramoplanin A2 and ramoplanose aglycon". Journal of the American Chemical Society.