Clavam

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Clavulanic acid Clavulanic acid.svg
Clavulanic acid

Clavams are a class of antibiotics. This antibiotic is derived from Streptomyces clavuligerus NRRL 3585. [1] Clavam is produced to form a new β-lactam antibiotic. [1] This class is divided into the clavulanic acid class and the 5S clavams class. Both groups are the outcomes of the fermentation process produced by Streptomyces spp. [2] 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. [3] Thus, they are also known as oxapenams.

An example is clavulanic acid, [4] from which this compound class receives its name.

Clavulanic acid, a type of clavam, has antibiotic properties. It can be used as a medication to treat a variety of bacterial infections. Clavam tablets may be effective for short-term treatment of bronchitis, cystitis, sinusitis, otitis media, or skin infections. [5] [6] Clavams are commonly used in conjunction with other antibiotics such as amoxicillin to produce a broader therapeutic effect. "One of the most valuable multipurpose and incredible trade of antibiotics is the β-lactams group. [7]

Clavulanic acid strongly inhibits β-lactamase in bacteria, which is associated with its antibiotic properties. β-Lactam antibiotics generally have a common feature which is the 3-carbon and 1-nitrogen ring (β-lactam ring) that is highly reactive. [8] Different molecules of the Clavam class have been shown to inhibit the action of several fungal species. 5S clavams do not have an inhibitory effect on β-lactamase, but are involved in methionine biosynthesis inhibition, making them bacteriostatic agents. [9] Additionally, 5S Clavams may have inhibitory effects on RNA synthesis, which is a common property of anti-fungal medications. [10] Clavams have wide-ranging bioactivity, and may have greater therapeutic use than current research indicates. [11] Because of their activity on β-lactamase, this class of antibiotics can evade antibiotic resistance in bacteria, which is a risk associated with other antibiotics such as penicillins.

Regulation of clavam-biosynthesis in S. clavuligerus

In S. Clavuligerus infection, a Streptomyces antibiotic regulatory protein known as cephamycin and clavulanic acid regulator (CcaR) is encoded into the cephamycin gene cluster. This is essential for the cephamycin C and clavulanic acid, but not the 5S claims. CcaR is important for the expression of polycistronic transcripts, which are early genes for clavulanic acid biosynthesis. This is also a key factor for activating its own transcription by binding to its own promoting region. [12]

Related Research Articles

<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">Cephamycin</span> Group of β-lactam antibiotics

Cephamycins are a group of β-lactam antibiotics. They are very similar to cephalosporins, and the cephamycins are sometimes classified as cephalosporins.

<span class="mw-page-title-main">DD-transpeptidase</span> Bacterial enzyme

DD-transpeptidase is a bacterial enzyme that catalyzes the transfer of the R-L-αα-D-alanyl moiety of R-L-αα-D-alanyl-D-alanine carbonyl donors to the γ-OH of their active-site serine and from this to a final acceptor. It is involved in bacterial cell wall biosynthesis, namely, the transpeptidation that crosslinks the peptide side chains of peptidoglycan strands.

<span class="mw-page-title-main">Cephem</span> Class of beta-lactam antibiotic

Cephems are a sub-group of β-lactam antibiotics including cephalosporins and cephamycins. It is one of the most common 4-membered ring heterocycle. Produced by actinomycetes, cephamycins were found to display antibacterial activity against a wide range of bacteria, including those resistant to penicillin and cephalosporins. The antimicrobial properties of Cephem include the attachment to certain penicillin-binding proteins that are involved in the production of cell walls of bacteria.

<span class="mw-page-title-main">Clavulanic acid</span> Molecule used 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">Ticarcillin</span> Antibiotic medication

Ticarcillin is a carboxypenicillin. It can be sold and used in combination with clavulanate as ticarcillin/clavulanic acid. Because it is a penicillin, it also falls within the larger class of β-lactam antibiotics. Its main clinical use is as an injectable antibiotic for the treatment of Gram-negative bacteria, particularly Pseudomonas aeruginosa and Proteus vulgaris. It is also one of the few antibiotics capable of treating Stenotrophomonas maltophilia infections.

<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.

Streptomyces clavuligerus is a species of Gram-positive bacterium notable for producing clavulanic acid.

<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.

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

Thienamycin 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.

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.

A ureohydrolase is a type of hydrolase enzyme. The ureohydrolase superfamily includes arginase, agmatinase, formiminoglutamase and proclavaminate amidinohydrolase. These enzymes share a 3-layer alpha-beta-alpha structure, and play important roles in arginine/agmatine metabolism, the urea cycle, histidine degradation, and other pathways.

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

Avibactam is a non-β-lactam β-lactamase inhibitor developed by Actavis jointly with AstraZeneca. A new drug application for avibactam in combination with ceftazidime was approved by the FDA on February 25, 2015, for treating complicated urinary tract (cUTI) and complicated intra-abdominal infections (cIAI) caused by antibiotic resistant-pathogens, including those caused by multi-drug resistant Gram-negative bacterial pathogens.

Fungal isolates have been researched for decades. Because fungi often exist in thin mycelial monolayers, with no protective shell, immune system, and limited mobility, they have developed the ability to synthesize a variety of unusual compounds for survival. Researchers have discovered fungal isolates with anticancer, antimicrobial, immunomodulatory, and other bio-active properties. The first statins, β-Lactam antibiotics, as well as a few important antifungals, were discovered in fungi.

Streptomyces isolates have yielded the majority of human, animal, and agricultural antibiotics, as well as a number of fundamental chemotherapy medicines. Streptomyces is the largest antibiotic-producing genus of Actinomycetota, producing chemotherapy, antibacterial, antifungal, antiparasitic drugs, and immunosuppressants. Streptomyces isolates are typically initiated with the aerial hyphal formation from the mycelium.

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.

<i>Streptomyces olivaceus</i> Species of bacterium

Streptomyces olivaceus is a bacterium species from the genus of Streptomyces which has been isolated from soil. Streptomyces olivaceus produces granaticin, elloramycin, tetroazolemycin A and tetroazolemycin B. Streptomyces olivaceus can be used to produce vitamin B12.

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

Vaborbactam (INN) is a non-β-lactam β-lactamase inhibitor discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an antibiotic by itself, it restores potency to existing antibiotics by inhibiting the β-lactamase enzymes that would otherwise degrade them. When combined with an appropriate antibiotic it can be used for the treatment of gram-negative bacterial infections.

References

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  2. Jensen, Susan E (2012-10-01). "Biosynthesis of clavam metabolites". Journal of Industrial Microbiology and Biotechnology. pp. 1407–1419. doi:10.1007/s10295-012-1191-0 . Retrieved 2024-02-11.
  3. "Medscape.com" . Retrieved 2008-12-29.
  4. Chemical Research Laboratory, Oxford University (The Schofield Group). "Antibiotic Biosynthesis, Clavulanic Acid Mode of Action and Biosynthesis". Archived from the original on 2011-06-05. Retrieved 2011-07-25.
  5. CLAVAM
  6. "Clavam". NPS MedicineWise. 8 September 2020. Retrieved 2021-04-29.
  7. Chmielewski, Marek; Cierpucha, Maciej; Kowalska, Patrycja; Kwit, Marcin; Frelek, Jadwiga (2008-05-15). "Structure–chiroptical properties relationship in clavams: An experimental and theoretical study". Chirality. 20 (5): 621–627. doi:10.1002/chir.20484. ISSN   0899-0042. PMID   17924419.
  8. Pandey, Neelanjana; Cascella, Marco (2022), "Beta Lactam Antibiotics", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   31424895 , retrieved 2022-04-04
  9. Jensen, Susan E (2012-10-01). "Biosynthesis of clavam metabolites". Journal of Industrial Microbiology and Biotechnology. 39 (10): 1407–1419. doi: 10.1007/s10295-012-1191-0 . ISSN   1476-5535. PMID   22948564. S2CID   2974684.
  10. Röhl, F.; Rabenhorst, J.; Zähner, H. (1987-05-01). "Biological properties and mode of action of clavams". Archives of Microbiology. 147 (4): 315–320. Bibcode:1987ArMic.147..315R. doi:10.1007/BF00406126. ISSN   1432-072X. PMID   3304182. S2CID   23725763.
  11. Cierpucha, Maciej; Panfil, Irma; Danh, Tong Thanh; Chmielewski, Marek; Kurzatkowski, Wieslaw; Rajnisz, Aleksandra; Solecka, Jolanta (October 2007). "Synthesis of 3-Substituted-clavams: Antifungal Properties, DD -Peptidase and β-Lactamase Inhibition". The Journal of Antibiotics. 60 (10): 622–632. doi: 10.1038/ja.2007.80 . ISSN   1881-1469. PMID   17965478.
  12. E Jensen, Susan (2012). "Biosynthesis of clavam metabolites". Journal of Industrial Microbiology & Biotechnology. 39 (10): 1407–1419. doi: 10.1007/s10295-012-1191-0 . PMID   22948564. S2CID   2974684.