Tetracyclines

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Tetracyclines or tetracyclines are antibiotic drugs that are produced by bacteria of the genus Streptomyces . Some of the pharmaceutical products are manufactured semi-synthetically, whereby the starting material is changed through organic chemical reactions. Tetracyclines have a bacteriostatic effect by inhibiting bacterial protein synthesis on the ribosomes and thus the growth of gram-positive , gram-negative and numerous bacteria without cell walls .

General structural formula of the tetracyclines

history

As the first representative of the tetracyclines, chlortetracycline was isolated by Benjamin Minge Duggar in 1948 as a metabolic product of the bacterium Streptomyces aureofaciens, which occurs mainly in soils , and named as aureomycin. In 1950, AC Finlay and his colleagues published their successful discovery at Pfizer of another tetracycline, which was obtained from the soil bacterium Streptomyces rimosus and was initially called terramycin, but was later renamed oxytetracycline . A research team from Pfizer succeeded in determining the structure of terramycin and aureomycin, published in 1952. Shortly afterwards, Lloyd Hillyard Conover synthesized tetracycline by dechlorinating aureomycin on the basis of these findings , the first ever synthesis of an antibiotic. Through further development, the group of tetracyclines was supplemented by further active ingredients (e.g. the group of glycylcyclines ).

chemistry

Tetracyclines are natural products that are synthesized by Streptomycetes using the polyketide route . Here, the basic structure of the four carbon six-membered rings is formed from acyl-CoA molecules (see general structural formula).

Streptomyces aureofaciens could already beidentifiedas a producer of chlortetracycline in 1948. If this bacterium is grown in a low-chloride medium, it produces the therapeutically used tetracycline . Streptomyces rimosus is suitablefor the production of oxytetracyclines and other tetracyclines.

Doxycycline and minocycline are semi-synthetic derivatives that can be made from oxytetracycline. They differ from other tetracyclines in their pharmacokinetic properties, such as better lipid solubility and accumulation in the central nervous system and in the skin . Rolitetracycline is a water-soluble prodrug of tetracycline with a modified amide group in position 2.

Another development led to the glycylcyclines, which have an improved spectrum of resistance.

pharmacology

Mechanism of action

Like macrolides , lincosamides , aminoglycosides and chloramphenicol , the tetracyclines inhibit protein biosynthesis on the bacterial ribosomes. The tetracyclines prevent the aminoacyl-tRNA from attaching to the acceptor sites of the 30S subunit of the ribosomes and thus prevent the peptide chain from being extended. Their low toxicity for humans can be explained by the selectivity for bacterial ribosomes over eukaryotic ribosomes.

Spectrum of activity

Tetracyclines have a bacteriostatic effect on gram-positive (e.g. staphylococci and streptococci ) and gram-negative bacteria (e.g. Brucella , Campylobacter and Neisseria ). Their effectiveness in combating problem germs without cell walls (e.g. mycoplasma , rickettsiae and chlamydia ) and spirochetes (e.g. Borrelia and treponema ) is of particular importance . Some tetracyclines also have clinical efficacy against Plasmodium ( malaria ) and against mycobacteria ( tuberculosis , leprosy ).

Resistances

Resistant germs occur especially in hospitals : In particular, numerous Proteus and Enterobacter species no longer respond to tetracyclines. Most Pseudomonas aeruginosa are also considered to be resistant.

The relatively new tigecycline (Tygacil ® ) is the first representative of the innovative class of glycylcyclines. Tigecycline bypasses the two major resistance mechanisms in this class of antibiotics: the efflux pump and ribosomal protection mechanisms.

Side effects

The side effects of tetracyclines are due in particular to their strong calcium- binding properties. Tetracyclines should therefore not be used in pregnant women , breastfeeding women or children in the growth phase because they are built into the bones and teeth , which leads to yellowing of the teeth, increased susceptibility to tooth decay and increased bone fractures , especially in newborns . Tetracyclines are excreted in breast milk .

Due to their broad spectrum of activity, they also decimate the natural colonization flora to a relatively large extent and not infrequently lead to pseudomembranous colitis as well as changes in the vaginal microbial flora and infections with Candida albicans ( fungal infection ).

They can also lead to photosensitization of the skin and, like many other drugs, to unspecific abdominal and head complaints (here: dizziness ). A further side effect may be a rash and itching , which will go away about two days after stopping the drug. A hepatotoxic effect that can be observed after administration of high doses of tetracycline can possibly be attributed to an interaction of the tetracyclines with the bacteria-like ribosomes of the mitochondria .

Tetracycline may have ototoxic side effects, especially on the sensory cells of the cochlea, which can be manifested in ringing in the ears and ringing in the ears ( tinnitus ). They are also considered a risk factor for excess brain pressure .

Pharmacokinetics

Doxycycline and minocycline are normally absorbed in the intestine by 90% (tetracycline: 80%) and excreted mainly via the bile , but also via the kidneys with a half-life of 15 hours (tetracycline: 9 hours).

The dose range for adults is usually between 100 and 200 milligrams per day for doxycycline, and around 2 mg / kg body weight for children.

Interactions

Tetracyclines can be bound by polyvalent metal ions (e.g. Ca 2+ , Mg 2+ and Fe 3+ ). Tetracyclines should therefore not be taken together with calcium carriers ( milk ) so as not to hinder their absorption in the intestine . Also, magnesium , iron and aluminum (antacids) form complex compounds (chelates) with the tetracyclines.

The effectiveness of the contraceptive pill is not guaranteed when tetracycline is taken.

Examples

Individual evidence

  1. ↑ Benjamin Duggar, et al. (1948): Aureomycin, a product of the continuing search for new antibiotics . In: Annals of the New York Academy of Sciences . Vol. 51, pp. 177-181; PMID 18112227 .
  2. ↑ AC Finlay, et al. (1950): Terramycin, a New Antibiotic. In: Science . Vol. 111, p. 85; PMID 15400447 .
  3. ↑ Stephens CR, Conover LH, Hochstein FA, et al. (1952): TERRAMYCIN. VIII. STRUCTURE OF AUREOMYCIN AND TERRAMYCIN . In: Journal of the American Chemical Society . Vol. 74, pp. 4976-4977; doi: 10.1021 / ja01139a533 .
  4. ^ Inventor of the Week: Lloyd Conover
  5. ↑ TV Budkevich, AV El skaya, KH Nierhaus: Features of 80S mammalian ribosome and its subunits. In: Nucleic Acids Research . 36, 2008, pp. 4736-4744, doi : 10.1093 / nar / gkn424 , PMC 2504317 (free full text).

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