Glycopeptide antibiotic

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Glycopeptide
Drug class
Vancomycin.svg
Vancomycin, a glycopeptide
Class identifiers
UseBacterial infection
ATC code J01X
Biological target inhibit peptidoglycan synthesis
Clinical data
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In Wikidata

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.

Contents

Mechanism and classification

Some members of this class of drugs inhibit the synthesis of cell walls in susceptible microbes by inhibiting peptidoglycan synthesis. The core class (including vancomycin) binds to acyl-D-alanyl-D-alanine in lipid II, preventing the addition of new units to the peptidoglycan. [1] Of this core class, one may distinguish multiple generations: the first generation includes vancomycin and teicoplanin, while the semisynthetic second generation includes lipoglycopeptides like telavancin, oritavancin and dalbavancin. The extra lipophilicity not only enhances Lipid II binding but also creates a second mechanism of action whereby the antibiotic dissolves into the membrane and makes it more permeable. [1]

Corbomycin and complestatin are structurally and ancestrally related to vancomycin, but they work by inhibiting autolysins through binding to peptidoglycan, therefore preventing cell division, [2] neither is an approved drug.

Ramoplanin, although a "glycopeptide" in the literal sense, has a quite different structural core. It not only binds to Lipid II but also attacks MurG and transglycosylases (glycosyltransferases) which polymerize amino acid/sugar building blocks into peptidoglycan. [1] It has been described as a "first-in-class" antibiotic, representing glycolipodepsipeptide antibiotics. [3]

Bleomycin also has a different core. Its mode of action is also unrelated to the cell wall, instead causing DNA damage in tumor cells. [4]

Use

Due to their toxicity, the use of first-generation glycopeptide antibiotics is restricted to patients who are critically ill, who have a demonstrated hypersensitivity to the β-lactams, or who are infected with β-lactam-resistant species, as in the case of methicillin-resistant Staphylococcus aureus. These antibiotics are effective principally against Gram-positive cocci. First-generation examples exhibit a narrow spectrum of action and are bactericidal only against the enterococci. Some tissues are not penetrated very well by glycopeptides, and they do not penetrate into the cerebrospinal fluid.

The second-generation glycopeptides, or "lipoglycopeptides", have better binding to Lipid II due to the lipophilic moieties, expanding the antibacterial spectrum. Telavancin also has a hydrophilic moiety attached to enhance tissue distribution and reduce nephrotoxicity. [1]

History

Vancomycin was isolated in 1953 and used clinically by 1958, while teicoplanin was discovered in 1978 and became clinically-available in 1984. [5] Telavancin is a semi-synthetic lipoglycopeptide derivative of vancomycin approved by FDA in 2009.[ citation needed ]

Teicoplanin has historically been more widely marketed - and thus more used - in Europe compared to the U.S. It has more fatty acid chains than vancomycin and is considered to be 50 to 100 times more lipophilic. Teicoplanin also has an increased half-life compared to vancomycin, as well as having better tissue penetration. It can be two to four times more active than vancomycin, but it does depend upon the organism. Teicoplanin is more acidic, forming water-soluble salts, so it can be given intramuscularly. Teicoplanin is much better at penetrating leukocytes and phagocytes than vancomycin.[ citation needed ]

Since 2002, isolates of vancomycin-resistant Staphylococcus aureus (VRSA) have been found in the USA and other countries.[ citation needed ]

Glycopeptides have typically been considered the last effective line of defense for cases of MRSA, however, several newer classes of antibiotics have proven to have activity against MRSA- including, in 2000, linezolid of the oxazolidinone class, and in 2003 daptomycin of the lipopeptide class. [6]

Research

Several derivatives of vancomycin are currently being developed, including oritavancin and dalbavancin (both lipoglycopeptides). Possessing longer half-lives than vancomycin, these newer candidates may demonstrate improvements over vancomycin due to less frequent dosing and activity against vancomycin-resistant bacteria. [7]

Administration

Vancomycin is usually given intravenously, as an infusion, and can cause tissue necrosis and phlebitis at the injection site if given too rapidly. Pain at the site of injection is indeed a common adverse event. One of the side effects is red man syndrome, an idiosyncratic reaction to bolus caused by histamine release. Some other side-effects of vancomycin are nephrotoxicity including kidney failure and interstitial nephritis, blood disorders including neutropenia, and deafness, which is reversible once therapy has stopped. Over 90% of the dose is excreted in the urine, therefore there is a risk of accumulation in patients with renal impairment, so therapeutic drug monitoring (TDM) is recommended.[ citation needed ]

Oral preparations of vancomycin are available, however, they are not absorbed from the lumen of the gut, so are of no use in treating systemic infections. The oral preparations are formulated for the treatment of infections within the gastrointestinal tract, Clostridioides difficile , for example.[ citation needed ]

Related Research Articles

<i>Staphylococcus aureus</i> Species of gram-positive bacterium

Staphylococcus aureus is a gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive for catalase and nitrate reduction and is a facultative anaerobe, meaning that it can grow without oxygen. Although S. aureus usually acts as a commensal of the human microbiota, it can also become an opportunistic pathogen, being a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains often promote infections by producing virulence factors such as potent protein toxins, and the expression of a cell-surface protein that binds and inactivates antibodies. S. aureus is one of the leading pathogens for deaths associated with antimicrobial resistance and the emergence of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA). The bacterium is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

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

Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously to treat 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 to treat Clostridioides difficile infections. When taken orally, it is poorly absorbed.

Methicillin-resistant <i>Staphylococcus aureus</i> Bacterium responsible for difficult-to-treat infections in humans

Methicillin-resistant Staphylococcus aureus (MRSA) is a group of gram-positive bacteria that are genetically distinct from other strains of Staphylococcus aureus. MRSA is responsible for several difficult-to-treat infections in humans. It caused more than 100,000 deaths worldwide attributable to antimicrobial resistance in 2019.

<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">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.

Vancomycin-resistant <i>Staphylococcus aureus</i> Antibiotica resistant bacteria

Vancomycin-resistant Staphylococcus aureus (VRSA) are strains of Staphylococcus aureus that have acquired resistance to the glycopeptide antibiotic vancomycin. Bacteria can acquire resistance genes either by random mutation or through the transfer of DNA from one bacterium to another. Resistance genes interfere with the normal antibiotic function and allow bacteria to grow in the presence of the antibiotic. Resistance in VRSA is conferred by the plasmid-mediated vanA gene and operon. Although VRSA infections are uncommon, VRSA is often resistant to other types of antibiotics and a potential threat to public health because treatment options are limited. VRSA is resistant to many of the standard drugs used to treat S. aureus infections. Furthermore, resistance can be transferred from one bacterium to another.

<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">Oxacillin</span> Chemical compound

Oxacillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class developed by Beecham.

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

Oritavancin, sold under the brand name Orbactiv among others, is a semisynthetic glycopeptide antibiotic medication for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.

<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.

Targanta Therapeutics Corporation was a biopharmaceutical company headquartered in Cambridge, Massachusetts. The company also had operations in Indianapolis, Montreal and Toronto. Targanta completed its initial public offering on October 9, 2007 and traded on the Nasdaq market under the symbol: TARG. Targanta was acquired by The Medicines Company in 2009.

<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">Telavancin</span> Pharmaceutical drug

Telavancin is a bactericidal lipoglycopeptide for use in MRSA or other Gram-positive infections. Telavancin is a semi-synthetic derivative of vancomycin.

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

Arbekacin (INN) is a semisynthetic aminoglycoside antibiotic which was derived from kanamycin. It is primarily used for the treatment of infections caused by multi-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Arbekacin was originally synthesized from dibekacin in 1973 by Hamao Umezawa and collaborators. It has been registered and marketed in Japan since 1990 under the trade name Habekacin. Arbekacin is no longer covered by patent and generic versions of the drug are also available under such trade names as Decontasin and Blubatosine.

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

Ceftaroline fosamil (INN), brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria. It retains some activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria, but its effectiveness is relatively much weaker. It is currently being investigated for community-acquired pneumonia and complicated skin and skin structure infection.

<span class="mw-page-title-main">Lipoglycopeptide</span> Class of chemical compounds

Lipoglycopeptides are a class of antibiotic that have lipophilic side-chains linked to glycopeptides. The class includes oritavancin, telavancin and dalbavancin.

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

Sophoraflavanone G is a volatile phytoncide, released into the atmosphere, soil and ground water, by plants of the genus Sophora. Species include Sophora pachycarpa and Sophora exigua, all found to grow within the United States in a variety of soil types, within temperate conditions, no lower than 0 °F. Sophoraflavanone G is released in order to protect the plant against harmful protozoa, bacteria, and fungi. Sophoraflavanone G, also called kushenin, is a flavonoid compound.

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.

References

  1. 1 2 3 4 Sarkar, P; Yarlagadda, V; Ghosh, C; Haldar, J (1 March 2017). "A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics". MedChemComm. 8 (3): 516–533. doi:10.1039/c6md00585c. PMC   6072328 . PMID   30108769.
  2. ↑ Culp, Elizabeth J.; Waglechner, Nicholas; Wang, Wenliang; Fiebig-Comyn, Aline A.; Hsu, Yen-Pang; Koteva, Kalinka; Sychantha, David; Coombes, Brian K.; Van Nieuwenhze, Michael S.; Brun, Yves V.; Wright, Gerard D. (2020-02-12). "Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling". Nature. 578 (7796): 582–587. Bibcode:2020Natur.578..582C. doi:10.1038/s41586-020-1990-9. ISSN   1476-4687. PMID   32051588. S2CID   211089119.
  3. ↑ "Ramoplanin". go.drugbank.com.
  4. ↑ Solomon, Edward I.; Decker, Andrea; Lehnert, Nicolai (February 21, 2003). "Non-heme iron enzymes: Contrasts to heme catalysis". PNAS. 100 (7): 3589–3594. doi: 10.1073/pnas.0336792100 . PMC   152966 . PMID   12598659.
  5. ↑ Butler MS, Hansford KA, Blaskovich MA, Halai R, Cooper MA (September 2014). "Glycopeptide antibiotics: back to the future". J. Antibiot. 67 (9): 631–44. doi: 10.1038/ja.2014.111 . PMID   25118105.
  6. ↑ Loffler CA, Macdougall C (December 2007). "Update on prevalence and treatment of methicillin-resistant Staphylococcus aureus infections". Expert Rev Anti Infect Ther. 5 (6): 961–81. doi:10.1586/14787210.5.6.961. PMID   18039081. S2CID   6048074.
  7. ↑ Van Bambeke F. (August 2006). "Glycopeptides and glycodepsipeptides in clinical development: a comparative review of their antibacterial spectrum, pharmacokinetics and clinical efficacy". Curr Opin Investig Drugs. 7 (8): 740–9. PMID   16955686. http://www.facm.ucl.ac.be/Full-texts-FACM/Vanbambeke-2006-3.pdf
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