Ramoplanin

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Ramoplanin
Ramoplanin A2.svg
Structure of Ramoplanin A2, with the variable acyl sidechain in blue.
Clinical data
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.161.388 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C119H154ClN21O40
Molar mass 2554.10 g·mol−1
3D model (JSmol)
  • 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=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 X mark.svgN
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Ramoplanin (INN) is a glycolipodepsipeptide antibiotic drug derived from strain ATCC 33076 of Actinoplanes . [1] It is effective against Gram-positive bacteria. [2]

Contents

Medical 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, [3] 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. [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
4
NF
, i-PrOH, and then treatment with the acyl group and DMF. [8]

Related Research Articles

<span class="mw-page-title-main">Vancomycin</span> Antibiotic medication

Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is used intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken orally as a treatment for severe Clostridium difficile colitis. When taken orally it is poorly absorbed.

<span class="mw-page-title-main">Gentamicin</span> Antibiotic medication

Gentamicin is an aminoglycoside antibiotic used to treat several types of bacterial infections. This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis among others. It is not effective for gonorrhea or chlamydia infections. It can be given intravenously, by intramuscular injection, or topically. Topical formulations may be used in burns or for infections of the outside of the eye. It is often only used for two days until bacterial cultures determine what specific antibiotics the infection is sensitive to. The dose required should be monitored by blood testing.

<i>Clostridioides difficile</i> infection Disease caused by C. difficile bacteria

Clostridioides difficile infection, also known as Clostridium difficile infection, is a symptomatic infection due to the spore-forming bacterium Clostridioides difficile. Symptoms include watery diarrhea, fever, nausea, and abdominal pain. It makes up about 20% of cases of antibiotic-associated diarrhea. Antibiotics can contribute to detrimental changes in gut microbiota; specifically, they decrease short-chain fatty acid absorption which results in osmotic, or watery, diarrhea. Complications may include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis.

<span class="mw-page-title-main">Clindamycin</span> Antibiotic

Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media, and endocarditis. It can also be used to treat acne, and some cases of methicillin-resistant Staphylococcus aureus (MRSA). In combination with quinine, it can be used to treat malaria. It is available by mouth, by injection into a vein, and as a cream or a gel to be applied to the skin or in the vagina.

<span class="mw-page-title-main">Aztreonam</span> Chemical compound

Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as Pseudomonas aeruginosa. This may include bone infections, endometritis, intra abdominal infections, pneumonia, urinary tract infections, and sepsis. It is given by intravenous or intramuscular injection or by inhalation.

<span class="mw-page-title-main">Teicoplanin</span> Pharmaceutical drug

Teicoplanin is an semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall peptidoglycan synthesis. It is used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis.

<span class="mw-page-title-main">Glycopeptide antibiotic</span> Class of antibiotic drugs

Glycopeptide antibiotics are a class of drugs of microbial origin that are composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include the anti-infective antibiotics vancomycin, teicoplanin, telavancin, ramoplanin and decaplanin, corbomycin, complestatin and the antitumor antibiotic bleomycin. Vancomycin is used if infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected.

<span class="mw-page-title-main">Daptomycin</span> Antibiotic

Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms.

<span class="mw-page-title-main">Cefotaxime</span> Chemical compound

Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in humans it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, sepsis, gonorrhea, and cellulitis. It is given either by injection into a vein or muscle.

<span class="mw-page-title-main">Rifaximin</span> Antibiotic medication

Rifaximin, is a non-absorbable, broad spectrum antibiotic mainly used to treat travelers' diarrhea. It is based on the rifamycin antibiotics family. Since its approval in Italy in 1987, it has been licensed in over more than 30 countries for the treatment of a variety of gastrointestinal diseases like irritable bowel syndrome, and hepatic encephalopathy. It acts by inhibiting RNA synthesis in susceptible bacteria by binding to the RNA polymerase enzyme. This binding blocks translocation, which stops transcription. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals.

<span class="mw-page-title-main">Fosfomycin</span> Chemical compound

Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat lower urinary tract infections. It is not indicated for kidney infections. Occasionally it is used for prostate infections. It is generally taken by mouth.

<span class="mw-page-title-main">Dalbavancin</span> Antibiotic used to treat MRSA

Dalbavancin, sold under the brand names Dalvance in the US and Xydalba in the EU among others, is a second-generation lipoglycopeptide antibiotic medication. It belongs to the same class as vancomycin, the most widely used and one of the treatments available to people infected with methicillin-resistant Staphylococcus aureus (MRSA).

<span class="mw-page-title-main">Fidaxomicin</span> Antibiotic

Fidaxomicin, sold under the brand name Dificid among others, is the first member of a class of narrow spectrum macrocyclic antibiotic drugs called tiacumicins. It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis. Fidaxomicin is minimally absorbed into the bloodstream when taken orally, is bactericidal, and selectively eradicates pathogenic Clostridioides difficile with relatively little disruption to the multiple species of bacteria that make up the normal, healthy intestinal microbiota. The maintenance of normal physiological conditions in the colon may reduce the probability of recurrence of Clostridioides difficile infection.

Clostridium innocuum is an anaerobic, non-motile, gram-positive bacterium that reproduces by sporulation. While there are over 130 species of Clostridium, C. innocuum is the third most commonly isolated. Although it is not normally considered an aggressive human pathogen, it has been isolated in some disease processes. C. innocuum and other Clostridium line the oropharynx and gastrointestinal tract, and are considered normal gut flora.

<span class="mw-page-title-main">Rifalazil</span> Antibiotic

Rifalazil is an antibiotic substance that kills bacterial cells by blocking off the β-subunit in RNA polymerase. Rifalazil is used as a treatment for many different diseases. The most common are Chlamydia infection, Clostridium difficile associated diarrhea (CDAD), and tuberculosis (TB). Using rifalazil and the effects that coincide with taking rifalazil for treating a bacterial disease vary from person to person, as does any drug put into the human body. Food interactions and genetic variation are a few causes for the variation in side effects from the use of rifalazil. Its development was terminated in 2013 due to severe side effects.

<i>Clostridioides difficile</i> Species of bacteria

Clostridioides difficile is a bacterium known for causing serious diarrheal infections, and may also cause colon cancer. It is known also as C. difficile, or C. diff, and is a Gram-positive species of spore-forming bacteria. Clostridioides spp. are anaerobic, motile bacteria, ubiquitous in nature and especially prevalent in soil. Its vegetative cells are rod-shaped, pleomorphic, and occur in pairs or short chains. Under the microscope, they appear as long, irregular cells with a bulge at their terminal ends. Under Gram staining, C. difficile cells are Gram-positive and show optimum growth on blood agar at human body temperatures in the absence of oxygen. C. difficile is catalase- and superoxide dismutase-negative, and produces up to three types of toxins: enterotoxin A, cytotoxin B and Clostridioides difficile transferase. Under stress conditions, the bacteria produce spores that are able to tolerate extreme conditions that the active bacteria cannot tolerate.

Teixobactin is a peptide-like secondary metabolite of some species of bacteria, that kills some gram-positive bacteria. It appears to belong to a new class of antibiotics, and harms bacteria by binding to lipid II and lipid III, important precursor molecules for forming the cell wall.

<span class="mw-page-title-main">Lipid II</span> Chemical compound

Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a peptidoglycan, which is amphipathic and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial cell membrane. Lipid II must translocate across the cell membrane to deliver and incorporate its disaccharide-pentapeptide "building block" into the peptidoglycan mesh. Lipid II is the target of several antibiotics.

<span class="mw-page-title-main">Nosiheptide</span> Chemical compound

Nosiheptide is a thiopeptide antibiotic produced by the bacterium Streptomyces actuosus.

<span class="mw-page-title-main">Ridinilazole</span> Chemical compound

Ridinilazole is an investigational small molecule antibiotic being evaluated for oral administration to treat Clostridioides difficile infection (CDI). In vitro, it is bactericidal against C. difficile and suppresses bacterial toxin production; the mechanism of action is thought to involve inhibition of cell division. It has properties which are desirable for the treatment of CDI, namely that it is a narrow-spectrum antibiotic which exhibits activity against C. difficile while having little impact on other normal intestinal flora and that it is only minimally absorbed systemically after oral administration. At the time ridinilazole was developed, there were only three antibiotics in use for treating CDI: vancomycin, fidaxomicin, and metronidazole. The recurrence rate of CDI is high, which has spurred research into other treatment options with the aim to reduce the rate of recurrence.

References

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  2. 1 2 Lee VJ (2007-01-01). "7.22 - Anti-Gram Positive Agents of Natural Product Origins". In Taylor JB, Triggle DJ (eds.). Comprehensive Medicinal Chemistry. Vol. II. Oxford: Elsevier. pp. 653–671. doi:10.1016/b0-08-045044-x/00222-4. ISBN   978-0-08-045044-5.
  3. Fulco P, Wenzel RP (December 2006). "Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent". Expert Review of Anti-Infective Therapy. 4 (6): 939–945. doi:10.1586/14787210.4.6.939. PMID   17181409. S2CID   12881565.
  4. Scheinfeld N (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. 6 (1): 97–103. PMID   17373167.
  5. Balagopal A, Sears CL (October 2007). "Clostridium difficile: new therapeutic options". Current Opinion in Pharmacology. 7 (5): 455–458. doi:10.1016/j.coph.2007.05.007. PMID   17644040.
  6. Gerding DN, Muto CA, Owens RC (January 2008). "Treatment of Clostridium difficile infection". Clinical Infectious Diseases. 46 (Suppl 1): S32–S42. doi: 10.1086/521860 . PMID   18177219.
  7. Fang X, Tiyanont K, Zhang Y, Wanner J, Boger D, Walker S (January 2006). "The mechanism of action of ramoplanin and enduracidin". Molecular BioSystems. 2 (1): 69–76. doi:10.1039/b515328j. PMID   16880924.
  8. 1 2 3 Shin D, Rew Y, Boger DL (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. 101 (33): 11977–11979. doi: 10.1073/pnas.0401419101 . PMC   514419 . PMID   15175429.
  9. Hoertz AJ, Hamburger JB, Gooden DM, Bednar MM, McCafferty DG (January 2012). "Studies on the biosynthesis of the lipodepsipeptide antibiotic Ramoplanin A2". Bioorganic & Medicinal Chemistry. 20 (2): 859–865. doi:10.1016/j.bmc.2011.11.062. PMID   22222159.
  10. Jiang W, Wanner J, Lee RJ, Bounaud PY, Boger DL (February 2003). "Total synthesis of the ramoplanin A2 and ramoplanose aglycon". Journal of the American Chemical Society. 125 (7): 1877–1887. doi:10.1021/ja0212314. PMID   12580615.