Macrolide
Macrolides, also Makrolaktone are organic chemical ring-shaped molecules that contain an intramolecular ester group ( lactone ). Over 2000 naturally occurring, structurally heterogeneous and complex macrolides with 8-62 ring members ( as of 2002) are known. Macrolides are used in particular as metabolites in bacteria and fungi. Their biosynthesis is generally done via a polyketide pathway.
The unusual chemical structure of many natural products macrolides and their interesting drug properties, they can often be the focus of chemical and pharmaceutical research.
Mechanism of action
The site of action of macrolide antibiotics is the 50 S subunit of the bacterial 70 S ribosomes. They interfere with the synthesis process of proteins ( polypeptide chains ) during the so-called elongation phase of protein biosynthesis. Translocation of the normally synthesized peptidyl- tRNA from the acceptor to the donor site is blocked. This leads to the termination of protein synthesis, the incomplete polypeptide remains at an intermediate stage. This results in a bacteriostatic effect.
In addition, macrolide antibiotics have an anti-inflammatory and immune- modulating effect. Studies showed especially in an exacerbation of chronic obstructive pulmonary disease decreased cytokine production in the lungs after administration of a macrolide antibiotic.
Resistance
The primary route of bacterial resistance to macrolides is the post-transcriptional methylation of the 23 S bacterial ribosomal RNA. This acquired resistance is mediated either via plasmids or chromosomes, for example, by mutation, and results in cross-resistance to macrolides, lincosamides and streptogramins ( an MLS - resistant phenotype ).
Two different types of resistance are observed more rarely the production of drug -inactivating enzymes ( esterases or kinases ), and the production of active ATP - dependent efflux pump transporting the drug from the cell.
Azithromycin has been used to treat strep throat ( caused by group A streptococcal infection with Streptococcus pyogenes ) in penicillin - sensitive patients, however, are macrolide - resistant strains of group A streptococci are not uncommon. Cephalosporin is another option for these patients.
Side effects
Typical side effects of macrolides are gastrointestinal disturbances and allergic reactions ( incidence < 0.3%). Erythromycin and clarithromycin are metabolized via the cytochrome P450 isoenzyme CYP3A4 and inhibit it. Therefore, they may not be combined with other drugs that are also metabolized by CYP3A4, such as Theophylline, cyclosporine, or most statins ( except fluvastatin ). Macrolides, mainly erythromycin and clarithromycin, have also an effect of QT prolongation, which can lead to a torsade de pointes. Therefore, a combination with other drugs which lead to QT prolongation, contraindicated. Macrolides also show enterohepatisches recycling: the drug is absorbed in the intestine and transported to the liver to be excreted in the bile and then into the duodenum. This leads to an accumulation of the metabolite in the system, which triggers nausea (feeling sick ).
Representative
Important examples are:
- Macrolide antibiotics: erythromycin
- Clarithromycin
- Azithromycin
- Roxithromycin
- Josamycin
- Spiramycin
- Telithromycin
- Tylosin
- Fidaxomycin
- Nystatin
- Natamycin
- Amphotericin B
- Pimecrolimus
- Sirolimus
- Tacrolimus
- Zearalenone