Thienamycin

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Thienamycin
Thienamycin.png
Names
Preferred IUPAC name
(5R,6S)-3-[(2-Aminoethyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C11H16N2O4S/c1-5(14)8-6-4-7(18-3-2-12)9(11(16)17)13(6)10(8)15/h5-6,8,14H,2-4,12H2,1H3,(H,16,17)/t5-,6-,8-/m1/s1 Yes check.svgY
    Key: WKDDRNSBRWANNC-ATRFCDNQSA-N Yes check.svgY
  • InChI=1/C11H16N2O4S/c1-5(14)8-6-4-7(18-3-2-12)9(11(16)17)13(6)10(8)15/h5-6,8,14H,2-4,12H2,1H3,(H,16,17)/t5-,6-,8-/m1/s1
    Key: WKDDRNSBRWANNC-ATRFCDNQBH
  • O=C(O)/C1=C(\SCCN)C[C@H]2N1C(=O)[C@@H]2[C@H](O)C
Properties
C11H16N2O4S
Molar mass 272.32 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Thienamycin (also known as thienpenem) is one of the most potent naturally produced antibiotics known thus far, 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. Thienamycin is a zwitterion at pH 7. [1]

Contents

History

In 1976, fermentation broths obtained from the soil bacterium Streptomyces cattleya were found to be active in a screen for inhibitors of peptidoglycan biosynthesis. [2] [3] Initial attempts to isolate the active compound proved difficult due to its chemical instability. 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). [4]

Figure 1. The Structure of thienamycin (with systematic numbering Numberedthienamycin+.png
Figure 1. The Structure of thienamycin (with systematic numbering

Thienamycin was the first among the naturally occurring class of carbapenem antibiotics to be discovered and isolated. [3] 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.[ citation needed ]

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). [5] Although thienamycin binds to all of the penicillin-binding proteins (PBPs) in Escherichia coli , it preferentially binds to PBP-1 and PBP-2, which are both associated with the elongation of the cell wall. [6]

Unlike penicillins, which are rendered ineffective through rapid hydrolysis by the β-lactamase enzyme present in some strains of bacteria, thienamycin remains antimicrobially active. 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. [7]

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-aminoadipic acid by ACV synthetase (ACVS, a nonribosomal peptide synthetase) and then cyclization of this formed tripeptide by isopenicillin N synthetase (IPNS).[ citation needed ]

The gene cluster (thn) for the biosynthesis of thienamycin of S. cattleya was identified and sequenced in 2003, lending insight into the biosynthetic mechanism for thienamycin formation. [8] The biosynthesis is thought to share features with the biosynthesis of the simple carbapenems, beginning with the condensation of malonyl-CoA with glutamate-5-semialdehyde to form the pyrroline ring. The β-lactam is then formed by a β-lactam synthetase, which makes use of ATP, providing a carbapenam. At some later point, oxidation to the carbapenem and ring inversions must occur.[ citation needed ]

The hydroxyethyl side chain of thienamycin is thought to be a result of two separate methyl transfers from S-adenosyl methionine. [9] According to the proposed gene functions, ThnK, ThnL, and ThnP could catalyze these methyl-transfer steps. A β-lactam synthetase (ThnM) is thought to catalyze the formation of the β-lactam ring fused to the five-membered ring. How the cysteaminyl side-chain is incorporated is largely unknown, although ThnT, ThnR, and ThnH are involved in the processing of CoA to cysteamine for use in the pathway. [10] Various oxidations complete the biosynthesis.[ citation needed ]

Total synthesis

Figure 3. Total Synthesis of (+)-Thienamycin Totalsynthesisofthienamycin.png
Figure 3. Total Synthesis of (+)-Thienamycin
Figure 4. Stereoselective Formation of the Lactam Ring Stereoselectivelactamformation4thienamycin.png
Figure 4. Stereoselective Formation of the Lactam Ring

Due to low titre and to difficulties in isolating and purifying thienamycin produced by 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 [11] is given in Figure 3.

The starting β-lactam for the pathway given above can be synthesized using the following method (Figure 4): [12]

Clinical use

Since thienamycin decomposes in the presence of water, it is impractical for the clinical treatment of bacterial infections, so stable derivatives were created for medicinal consumption. One such derivative, imipenem, was formulated in 1985. Imipenem, an N-formimidoyl derivative of thienamycin, is rapidly metabolized by a renal dipeptidase enzyme found in the human body. To prevent its rapid degradation, imipenem is normally coadministered with cilastatin, an inhibitor of this enzyme.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Beta-lactam</span> Family of chemical compounds

A beta-lactam (β-lactam) ring is a four-membered lactam. A lactam is a cyclic amide, and beta-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone. β-lactams are significant structural units of medicines as manifested in many β-lactam antibiotics Up to 1970, most β-lactam research was concerned with the penicillin and cephalosporin groups, but since then, a wide variety of structures have been described.

<span class="mw-page-title-main">Beta-lactamase</span> Class of enzymes

Beta-lactamases (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam (β-lactam) ring. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.

<span class="mw-page-title-main">Penicillin</span> Group of antibiotics derived from Penicillium fungi

Penicillins are a group of β-lactam antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G and penicillin V. Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use.

<span class="mw-page-title-main">Beta-lactam antibiotics</span> Class of broad-spectrum antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

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

Methicillin (USAN), also known as meticillin (INN), is a narrow-spectrum β-lactam antibiotic of the penicillin class.

<span class="mw-page-title-main">Cephalosporin</span> Class of pharmaceutical drugs

The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as Cephalosporium.

<span class="mw-page-title-main">Meropenem</span> Broad-spectrum antibiotic

Meropenem, sold under the brand name Merrem among others, is an intravenous β-lactam antibiotic used to treat a variety of bacterial infections. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax.

<span class="mw-page-title-main">Clavulanic acid</span> Β-lactam molecule used as β-lactamase inhibitor to overcome antibiotic resistance in bacteria

Clavulanic acid is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins.

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

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

<span class="mw-page-title-main">Carbapenem</span> Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for the treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta-lactam antibiotics drug class, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

<span class="mw-page-title-main">Imipenem</span> Carbapenem antibiotic

Imipenem is an intravenous β-lactam antibiotic discovered by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s. Carbapenems are highly resistant to the β-lactamase enzymes produced by many multiple drug-resistant Gram-negative bacteria, thus playing a key role in the treatment of infections not readily treated with other antibiotics.

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

Dicloxacillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible (non-resistant) Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most penicillins. Dicloxacillin is available under a variety of trade names including Diclocil (BMS).

<span class="mw-page-title-main">Penicillin-binding proteins</span> Class of proteins

Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics bind to PBPs, which are essential for bacterial cell wall synthesis. PBPs are members of a subgroup of enzymes called transpeptidases. Specifically, PBPs are DD-transpeptidases.

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

Doripenem is an antibiotic drug in the carbapenem class. It is a beta-lactam antibiotic drug able to kill Pseudomonas aeruginosa.

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

Cefoxitin is a second-generation cephamycin antibiotic developed by Merck & Co., Inc. from Cephamycin C in the year following its discovery, 1972. It was synthesized in order to create an antibiotic with a broader spectrum. It is often grouped with the second-generation cephalosporins. Cefoxitin requires a prescription and as of 2010 is sold under the brand name Mefoxin by Bioniche Pharma, LLC. The generic version of cefoxitin is known as cefoxitin sodium.

β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

<span class="mw-page-title-main">Clavam</span> Class of antibiotics

Clavams are a class of antibiotics. This antibiotic is derived from Streptomyces clavuligerus NRRL 3585. Clavam is produced to form a new β-lactam antibiotic. This class is divided into the clavulanic acid class and the 5S clavams class. Clavulanic acid is a broad-spectrum antibiotic and 5S clavams may have anti-fungal properties. They are similar to penams, but with an oxygen substituted for the sulfur. Thus, they are also known as oxapenams.

Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

Carbapenem-resistant Enterobacteriaceae (CRE) or carbapenemase-producing Enterobacteriaceae (CPE) are Gram-negative bacteria that are resistant to the carbapenem class of antibiotics, considered the drugs of last resort for such infections. They are resistant because they produce an enzyme called a carbapenemase that disables the drug molecule. The resistance can vary from moderate to severe. Enterobacteriaceae are common commensals and infectious agents. Experts fear CRE as the new "superbug". The bacteria can kill up to half of patients who get bloodstream infections. Tom Frieden, former head of the Centers for Disease Control and Prevention has referred to CRE as "nightmare bacteria". Examples of enzymes found in certain types of CRE are KPC and NDM. KPC and NDM are enzymes that break down carbapenems and make them ineffective. Both of these enzymes, as well as the enzyme VIM have also been reported in Pseudomonas.

Streptomyces cattleya is a Gram-positive bacterium which makes cephamycin, penicillin and thienamycin. The bacterium expresses a fluorinase enzyme, and the organism has been used to understand the biosynthesis of fluoroacetate and the antibacterial 4-fluoro-L-threonine. The γ-Glu-βes pathway to biosynthesis of non-traditional amino acids β-ethynylserine (βes) and L-propargylglycine (Pra) was first characterized in this species.

References

  1. ↑ Nicolaou, K.C.; Sorensen, Erik (1996). Classics in Total Synthesis . VCH Publishers. pp.  255, 260. ISBN   3-527-29231-4.
  2. ↑ 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.{{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  3. 1 2 Silver, L.L (2011). "Chapter 2, Rational approaches to antibiotic discovery: pre-genomic directed and phenotypic screening". In Dougherty, T.; Pucci, M.J. (eds.). Antibiotic Discovery and Development . Springer. pp.  46–47. doi:10.1007/978-1-4614-1400-1_2. ISBN   978-1-4614-1400-1.
  4. ↑ 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. doi: 10.7164/antibiotics.32.1 . PMID   761989.
  5. ↑ 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. doi:10.1016/S0924-8579(98)00094-6. PMID   10221411.
  6. ↑ 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. doi:10.1128/aac.12.3.406. PMC   429926 . PMID   334066.
  7. ↑ 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. doi:10.1093/jac/6.5.601. PMID   6967870.
  8. ↑ 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. doi: 10.1016/S1074-5521(03)00069-3 . hdl: 10651/28518 . PMID   12725858.
  9. ↑ 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 (17): 5365–5366. doi:10.1021/ja00277a063.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ↑ Freeman MF, Moshos KA, Bodner MJ, Li R, Townsend CA (2008). "Four enzymes define the incorporation of coenzyme A in thienamycin biosynthesis". Proc. Natl. Acad. Sci. USA. 105 (32): 11128–33. Bibcode:2008PNAS..10511128F. doi: 10.1073/pnas.0804500105 . PMC   2516261 . PMID   18678912.
  11. ↑ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ↑ 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. doi: 10.7164/antibiotics.53.1231 . PMID   11132974.
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