Thienamycin

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Thienamycin
IUPAC name	(5R,6S)-3-[(2-Aminoethyl)thio]-6-[(1R)-1- hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept- 2-ene-2-carboxylic acid
Identifiers
CAS number	[59995-64-1]
SMILES	CC(C1C2CC(=C(N2C1=O)C(=O)O)SCCN)O
Properties
Molecular formula	C11H16N2O4S
Molar mass	272.32 g/mol
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

Thienamycin, one of the most potent naturally-produced antibiotics known thus far, was discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes.

Contents 1 History 2 Mechanism of Action 3 Biosynthesis 4 Total Synthesis 5 Clinical Use 6 References

[edit] History

In 1976, fermentation broths obtained from the soil bacteria Streptomyces cattleya were found to be active in screens for inhibitors of peptidoglycan biosynthesis^[1]. Initial attempts to isolate the active species proved difficult due to the chemical instability of that component. After many attempts and extensive purification, the material was finally isolated in >90% purity, allowing for the structural elucidation of thienamycin in 1979 (Figure 1)^[2].

Thienamycin was the first among the naturally-occurring class of carbapenem antibiotics to be discovered and isolated. Carbapenems are similar in structure to their antibiotic “cousins” the penicillins. Like penicillins, carbapenems contain a β-lactam ring (cyclic amide) fused to a five-membered ring. Carbapenems differ in structure from penicillins in that within the five-membered ring a sulfur is replaced by a carbon atom (C1) and an unsaturation is present between C2 and C3 in the five-membered ring.

[edit] Mechanism of Action

In vitro, thienamycin employs a similar mode of action as penicillins through disrupting the cell wall synthesis (peptidoglycan biosynthesis) of various Gram-positive and Gram-negative bacteria (Staphylococcus aureus,Staphylococcus epidermidis, Pseudomonas aeruginosa to name a few)^[3]. In a study carried out by Spratt et al., they found that, although thienamycin binds to all of the penicillin-binding proteins (PBP) in Escherichia coli, it preferentially binds to PBP-1 and PBP-2, which are both associated with the elongation of the cell wall^[4].

Unlike pencillins, which are rendered ineffective through rapid hydrolysis by the β-lactamase enzyme present in some strains of bacteria, thienamycin remains antimicrobially active. Neu et al. found that thienamycin displayed high activity against bacteria that were resistant to other β-lactamase stable compounds (cephalosporins), highlighting the superiority of thienamycin as an antibiotic among β-lactams^[5].

[edit] Biosynthesis

The formation of thienamycin is thought to occur through a different pathway from classic β-lactams (penicillins, cephalosporins). Production of classic β-lactams in both fungi and bacteria occur through two steps: First, the condensation of L-cysteine, L-Valine, and L-α-amino adipic acid by ACV synthetase (ACVS, a nonribsomal peptide synthetase) and then cyclization of this formed tripeptide by isopenicillin N synthetase (IPNS).

The gene cluster (thn) for the biosynthesis of thienamycin by S. cattleya was identified and sequenced, finally, in 2003, lending insight into the biosynthetic mechanism for thienamycin formation^[6]. Based on previous work^[7] and on this significant breakthrough, a tentative biosynthetic pathway has been proposed (Figure 2).

The biosynthesis of thienamycin begins with the condensation of acetyl-S-CoA with γ-glutamyl phosphate to form the pyrroline ring. The hydroxyethyl side chain of thienamycin is thought to be a result of two separate methyl transfers from S-adenosyl methionine^[8]. According to the proposed biosynthesis, one methylation step occurs immediately after formation of the pyrroline ring, and the other methylation step occurs after formation of the bicyclic ring. According to the proposed gene functions (Table 1), ThnK, ThnL, and ThnP could catalyze these methyl-transfer steps. After the first methylation step occurs, β-lactam synthetase (ThnM) is thought to catalyze the formation of the β-lactam ring fused to the five-membered ring. Incorporation of the cysteaminyl side chain is then assisted by ThnV and/or ThnT. Oxidations occur between C6 and C8, followed by the second methylation step (mentioned above), then reduction at C6 and C8, and subsequently oxidation between C2 and C3. Hydroxylation by ThnG gives thienamycin as the final product (Note: see Figure 2 for a potential alternative pathway).

[edit] Total Synthesis

Due to low titre and to difficulties in isolating and purifying thienamycin produced via fermentation, total synthesis is the preferred method for commercial production. Numerous methods are available in the literature for the total synthesis of thienamycin. One synthetic route^[9] is given in Figure 3.

The starting β-lactam for the pathway given above can be synthesized via the following method (Figure 4):^[10]

[edit] Clinical Use

Thienamycin itself is extremely unstable and decomposes in aqueous solution. Consequently, thienamycin is impractical for clinical treatment of bacterial infections. For this reason, stable derivatives of thienamycin were created for medicinal consumption. One such derivative, imipenem, was formulated in 1985. Imipenem, an N-formimidoyl derivative of thienamycin, is rapidly metabolized by the renal dihydropeptidase enzyme found in the human body. To prevent its rapid degradation, imipenem is normally co-administered with cilastatin, an inhibitor of this enzyme.

[edit] References

1. ^ Kahan, JS, Kahan, FM, Goegelman, R., Currie, SA, Jackson, M., Stapley, EO, Miller, TW, Miller, AK, Hendlin, D., Mochales, S., Hernandez, S., Woodruff, HB. (1976). "Abstracts XVI, Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill." 227. 
2. ^ Kahan JS, Kahan FM, Goegelman R, et al (1979). "Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties". J. Antibiot. 32 (1): 1–12. PMID 761989. 
3. ^ Bradley JS, Garau J, Lode H, Rolston KV, Wilson SE, Quinn JP (1999). "Carbapenems in clinical practice: a guide to their use in serious infection". Int. J. Antimicrob. Agents 11 (2): 93–100. PMID 10221411. 
4. ^ Spratt BG, Jobanputra V, Zimmermann W (1977). "Binding of thienamycin and clavulanic acid to the penicillin-binding proteins of Escherichia coli K-12". Antimicrob. Agents Chemother. 12 (3): 406–9. PMID 334066. 
5. ^ Romagnoli MF, Fu KP, Neu HC (1980). "The antibacterial activity of thienamycin against multiresistant bacteria-comparison with beta-lactamase stable compounds". J. Antimicrob. Chemother. 6 (5): 601–6. PMID 6967870. 
6. ^ Núñez LE, Méndez C, Braña AF, Blanco G, Salas JA (2003). "The biosynthetic gene cluster for the beta-lactam carbapenem thienamycin in Streptomyces cattleya". Chem. Biol. 10 (4): 301–11. PMID 12725858. 
7. ^ Williamson JM, Inamine E, Wilson KE, Douglas AW, Liesch JM, Albers-Schönberg G (1985). "Biosynthesis of the beta-lactam antibiotic, thienamycin, by Streptomyces cattleya". J. Biol. Chem. 260 (8): 4637–47. PMID 3988730. 
8. ^ Houck, DR, Kobayashi, K., Williamson, JM, Floss, HG (1986). "Stereochemistry of methylation in thienamycin biosynthesis: example of a methyl transfer from methionine with retention of configuration". J. Am. Chem. Soc. 108: 5365–5366. doi:10.1021/ja00277a063. 
9. ^ Hanessian, S., Desilets, D., Bennani, YL. (1990). "A novel ring-closure strategy for the carbapenems: the total synthesis of (+)-thienamycin.". J. Org. Chem. 55 (10): 3098–3103. doi:10.1021/jo00297a026. 
10. ^ Tatsuta K, Takahashi M, Tanaka N, Chikauchi K (2000). "Novel synthesis of (+)-4-acetoxy-3-hydroxyethyl-2-azetidinone from carbohydrate. A formal total synthesis of (+)-thienamycin". J. Antibiot. 53 (10): 1231–4. PMID 11132974.