Macrolides

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The musk fragrance dihydroambrettolide as an example of a macrolide

Macrolides , also called macrolactones , are lactones with a higher number of ring members, in other words, macrocyclic compounds with an internal ester function . Over 2000 naturally occurring, structurally heterogeneous and complex macrolides with 8 to 62 ring members (as of 2002) are known. The macrolides include musk lactones. Macrolides are widely found in metabolic products of bacteria and fungi . Their biosynthesis usually takes place via a polyketide route.

Representative

Important representatives are:

Macrolide antibiotics

Macrolide antibiotics are a relatively new class of antibiotics from the macrolide class. They have a bacteriostatic effect by inhibiting the protein synthesis of bacteria ; only newer keto derivatives, of which only telithromycin has been approved so far (as of 2006) , have a bactericidal effect . The oldest representative of the macrolide antibiotics is erythromycin , in 1954 oleandomycin was isolated from culture filtrates of Streptomyces antibioticus. More modern substances are clarithromycin , azithromycin or roxithromycin . Tylosin is currently only approved for veterinary use. The lincosamides are related to the macrolides .

They are suitable against almost all bacterial infections in the respiratory tract [but not against tuberculosis (apart from clarithromycin)]. They are also the remedy of choice for two sex diseases that often occur together: gonorrhea and chlamydial infections . They are also used against skin infections caused by staphylococci .

Macrolide antibiotics include not only β-lactam antibiotics to well-tolerated antibiotics. They can cause mild gastrointestinal discomfort or reversible hearing impairment. Erythromycin has also been shown to be tolerated during pregnancy .

They can be given as a tablet . Compared to erythromycin, the newer representatives are better absorbed, stay longer in the body and are more effective. Macrolides are partly excreted by the liver and partly by the kidneys . However, macrolide antibiotics are not suitable for the treatment of urinary tract infections because they have a deficit in their effectiveness against Enterobacteriaceae such as E. coli, which are the most common pathogens causing urinary tract infections. They can also hinder the elimination of other medicines that are acids and are eliminated by the kidneys. These are u. a. Acetylsalicylic acid , uricosurics and uricostatics , uric acid , thiazide diuretics , penicillins , sulfonamides .

On the other hand, they are not among the most effective antibiotics and are therefore not suitable for difficult infections (e.g. in the intensive care unit ). Since they only inhibit one specific enzyme, resistance to macrolides quickly develops . Macrolides can also be used for community-acquired pneumonia.

Mechanism of action

The target of the macrolide antibiotics is the 50-S subunit of the bacterial 70-S ribosomes. In doing so, they hinder the synthesis process of proteins (polypeptide chains) during the elongation phase of protein biosynthesis. The translocation of the normally synthesized peptidyl-t-RNA from the acceptor site to the donor site is blocked. This leads to the termination of protein synthesis, the unfinished polypeptide remains at its intermediate level. This results in a bacteriostatic effect.

In addition, macrolide antibiotics have anti-inflammatory and immune-modulating effects. Studies have shown decreased cytokine production in the lungs after administration of a macrolide antibiotic , particularly in the event of an exacerbation of chronic obstructive pulmonary disease .

resistance

The primary pathway for bacterial resistance to macrolide antibiotics is post-transcriptional methylation of bacterial 23-S-ribosomal RNA . This acquired resistance is mediated either via plasmids or chromosomes , e.g. B. by mutation , and results in a cross resistance to macrolides, lincosamides and streptogramins (an MLS-resistant phenotype).

Two other seldom observed types of resistance are the production of drug-inactivating enzymes ( esterases or kinases ) and the production of active ATP -dependent efflux pumps that transport the drug out of the cell.

Azithromycin has been used to treat sore throats (caused by Streptococcus A infection with Streptococcus pyogenes ) in penicillin- sensitive patients, but macrolide-resistant strains of Streptococci A are not uncommon. Cephalosporin is another option for these patients.

Side effects

Typical side effects of macrolide antibiotics are gastrointestinal disorders and allergic reactions (frequency <0.3%). Erythromycin and clarithromycin are metabolized and inhibited by the cytochrome P450 isoenzyme CYP3A4 . Therefore, they must not be combined with other drugs that are also broken down by CYP3A4, such as: B. Theophylline , Ciclosporin or most statins (exception fluvastatin ). Macrolide antibiotics, mainly erythromycin and clarithromycin, cause a prolongation of the intraventricular excitation time ( QT syndrome ), which can lead to a torsade de pointes . Therefore, combination with other drugs that cause QT prolongation is contraindicated. Macrolide antibiotics also show enterohepatic recycling: the drug is absorbed in the intestine and transported to the liver, only to be excreted with the bile into the duodenum . This leads to an accumulation of the metabolic product in the system, which causes nausea .

Related links

Ansamycins are macrolide antibiotics that contain a lactam group instead of the lactone group, i.e. they are cyclic amides . The most important representatives are rifamycin , geldanamycin and maytansin .

literature

  • Satoshi Omura (Ed.): Macrolide Antibiotics - Chemistry, Biology, and Practice. 2nd Edition. Academic Press, Amsterdam / Boston / New York / Oxford et al. 2002, ISBN 0-12-526451-8 .

Individual evidence

  1. ↑ Telithromycin, a new antibiotic used to treat respiratory infections. In: Zeitschrift für Chemotherapie 6, 2001.
  2. ↑ Karl Wurm, AM Walter: Infectious Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition, ibid. 1961, pp. 9–223, here: p. 53.
  3. ↑ AWMF online - S3 guideline: Deep respiratory infections / pneumonia.
  4. ↑ K. Aktories, U. Förstermann, F. Hofmann, K. Starke: General and special pharmacology and toxicology. 9th edition. Urban & Fischer Verlag / Elsevier, Munich / Jena 2006, ISBN 3-437-44490-5 , p. 819.
  5. ^ Richard P. Wenzel, Alpha A. Fowler, Michael B. Edmond: Antibiotic Prevention of Acute Exacerbations of COPD. In: New England Journal of Medicine. 367, 2012, pp. 340-347.
  6. ↑ Sivakumar Sathasivam, B. Lecky: Statin induced myopathy . In: British Medical Journal . tape 337 , November 6, 2008, p. a2286 , doi : 10.1136 / bmj.a2286 , PMID 18988647 ( bmj.com ).
  7. ↑ Otto-Albrecht Neumüller (Ed.): Römpps Chemie-Lexikon. Volume 4: M-Pk. 8th revised and expanded edition. Franckh'sche Verlagshandlung, Stuttgart 1985, ISBN 3-440-04514-5 , p. 2468.