Ramoplanin (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

) is a glycolipodepsipeptide antibiotic drug derived from strain ATCC 33076 of ''

Actinoplanes ''Actinoplanes'' is a genus in the family Micromonosporaceae. They have aerial mycelia and spherical, motile spores. ''Actinoplanes'' species produce the pharmaceutically important compounds valienamine (a precursor to the antidiabetic drug acar ...

''. It is effective against

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

bacteria.

Mechanism

It exerts its bacteriocidal effect by inhibiting cell wall biosynthesis, acting by inhibiting the transglycosylation step of

peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ba ...

synthesis. Ramoplanin specifically binds to and sequesters lipid intermediates I and II, preventing intracellular glycosyltransferase (MurG) and other steps of the peptidoglycan assembly system.

Uses

Its development has been fast-tracked by the

U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

as a treatment for multiple antibiotic-resistant '' Clostridium difficile'' infection of the gastrointestinal tract, Unlike

vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, ...

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

Chemistry

Rapoplanin 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.

Synthesis

Biosynthesis

The biosynthesis is performed by a 33-gene cluster containing

nonribosomal peptide synthetase Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacter ...

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 were 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

{{Cell wall disruptive antibiotics Antibiotics