Ramoplanin

Ramoplanin (INN) is a glycolipodepsipeptide antibiotic drug derived from strain ATCC 33076 of Actinoplanes.^[1] It is effective against Gram-positive bacteria.^[2]

Ramoplanin

Structure of Ramoplanin A2, with the variable acyl sidechain in blue.
Clinical data
Routes of administration	Oral
ATC code	none
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	76168-82-6 Y
PubChem CID	16132338
ChemSpider	17286439 N
UNII	0WX9996O2G
KEGG	C12008 N
ChEBI	CHEBI:29670 N
ChEMBL	ChEMBL1095892 N
ECHA InfoCard	100.161.388
Chemical and physical data
Formula	C119H154ClN21O40
Molar mass	2554.10 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@@H]1C(=O)N[C@H](C(=O)O[C@@H]([C@@H](C(=O)N[C@@H](C(=O)N[C@@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N1)CC(C)C)c2ccc(cc2)O)[C@@H](C)O)c3ccc(cc3)O[C@@H]4[C@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O[C@@H]5[C@H]([C@H]([C@@H]([C@H](O5)CO)O)O)O)CCCN)Cc6ccccc6)[C@H](C)O)c7ccc(cc7)O)c8ccc(cc8)O)[C@@H](C)O)CCCN)c9ccc(cc9)O)NC(=O)[C@H](CC(=O)N)NC(=O)/C=C\C=C\CC(C)C)C(=O)N)c1ccc(c(c1)Cl)O
InChI InChI=1S/C119H154ClN21O40/c1-54(2)17-11-9-14-22-82(153)127-77(50-81(123)152)107(166)141-93-99(101(124)160)180-117(176)92(66-33-44-78(151)72(120)49-66)140-102(161)56(5)126-105(164)75(47-55(3)4)128-83(154)51-125-108(167)87(61-23-34-67(147)35-24-61)136-111(170)86(59(8)146)134-113(172)89(65-31-42-71(43-32-65)177-119-100(97(158)95(156)80(53-143)179-119)181-118-98(159)96(157)94(155)79(52-142)178-118)135-104(163)73(20-15-45-121)129-106(165)76(48-60-18-12-10-13-19-60)131-109(168)84(57(6)144)133-114(173)90(63-27-38-69(149)39-28-63)138-115(174)91(64-29-40-70(150)41-30-64)137-110(169)85(58(7)145)132-103(162)74(21-16-46-122)130-112(171)88(139-116(93)175)62-25-36-68(148)37-26-62/h9-14,18-19,22-44,49,54-59,73-77,79-80,84-100,118-119,142-151,155-159H,15-17,20-21,45-48,50-53,121-122H2,1-8H3,(H2,123,152)(H2,124,160)(H,125,167)(H,126,164)(H,127,153)(H,128,154)(H,129,165)(H,130,171)(H,131,168)(H,132,162)(H,133,173)(H,134,172)(H,135,163)(H,136,170)(H,137,169)(H,138,174)(H,139,175)(H,140,161)(H,141,166)/b11-9+,22-14-/t56-,57+,58-,59-,73-,74-,75+,76+,77+,79-,80-,84+,85-,86-,87+,88-,89+,90-,91+,92+,93+,94-,95-,96+,97+,98+,99+,100+,118-,119+/m1/s1 N Key:KGZHFKDNSAEOJX-WIFQYKSHSA-N N
NY (what is this?)  (verify)

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,^[3] 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.^[4][5][6]

Ramoplanin is "particularly useful" in cases E. faecalis no matter its sensitivity to vancomycin.^[2]

Mechanism of action

It exerts its bacteriocidal effect by inhibiting cell wall biosynthesis, acting by inhibiting the transglycosylation step of peptidoglycan synthesis.^[7] Ramoplanin specifically binds to and sequesters lipid intermediates I and II, preventing intracellular glycosyltransferase (MurG) and other steps of the peptidoglycan assembly system.^[8]

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.^{[8]: Fig. 1}

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.^[9]

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.^[10] 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 Bu
₄NF, i-PrOH, and then treatment with the acyl group and DMF.^[8]

• Ramoplanin A2 Aglycon Synthesis
• 
  1 - Synthesis of Hpg3-Phe9 Subunit
• 
  2 - Fmoc-L-HAsn(Trt)-Obn Preparation
• 
  3 - Synthesis of Depsipeptide subunit
• 
  4 - Synthesis of Orn10-Gly14 Subunit
• 
  5 - Preparation of acyl group
• 
  6 - Deprotection