Related Experiment Videos
Structure-activity relationships of ketolides vs. macrolides
1Department of Biochemistry and Molecular Biology, Odense University, Denmark. srd@bmb.sdu.dk
Abstract:
Since their discovery, the macrolide antimicrobials have proved clinically valuable for the treatment of respiratory tract infections, offering coverage against a broad spectrum of pathogens and excellent tolerability. However, the global increase in macrolide resistance among respiratory pathogens, particularly Streptococcus pneumoniae, threatens their future usefulness. The ketolides, of which telithromycin is the first to reach clinical development, represent a new generation of antimicrobials that have been developed with a view to overcoming the problem of macrolide resistance. Telithromycin is structurally derived from macrolides, and possesses several distinguishing features that are important for its improved microbiological profile. The L-cladinose at position C3 of the miacrolactone ring has been replaced with a keto function. This modification enables telithromycin to bind to its target without tripping the inducible resistance to macrolide-lincosamide-streptograminB (MLS(B)) drugs that many groups of pathogens exhibit. The C6 position has been modified by the addition of a methoxy group. This helps prevent hemiketalization of the C6 position with the 3- and 9-keto groups, thereby conferring excellent acid stability, particularly at gastric pH values. Telithromycin is differentiated from other ketolide compounds by the addition of a large aromatic N-substituted carbamate extension from positions C11/C12. This carbamate extension improves binding of the drug to its target, the 50S ribosomal subunit, as demonstrated in in vitro experiments. Telithromycin binds to wild-type ribosomes with 10-fold greater affinity than erythromycin A and 6-fold greater affinity than clarithromycin; its affinity for MLS(B)-resistant ribosomes is > 20 times that of both macrolides. The increased ribosomal affinity of telithromycin correlates with its superior potency against Gram-positive cocci both in vitro and in vivo, and is one of the factors determining the drug's activity against MLS(B)-resistant respiratory pathogens.
Insights
Telithromycin, a novel ketolide antibiotic, effectively combats macrolide-resistant respiratory pathogens by binding strongly to bacterial ribosomes. This new drug class offers a promising solution to increasing antimicrobial resistance, particularly for Streptococcus pneumoniae infections.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Macrolide antimicrobials are crucial for respiratory tract infections but face rising resistance from pathogens like Streptococcus pneumoniae.
- Macrolide resistance, particularly the macrolide-lincosamide-streptograminB (MLS(B)) type, limits treatment options for bacterial respiratory infections.
- A new generation of antimicrobials, ketolides, has been developed to address macrolide resistance.
Purpose of the Study:
- To introduce telithromycin, the first clinically developed ketolide, designed to overcome macrolide resistance mechanisms.
- To elucidate the structural modifications of telithromycin that confer improved microbiological activity and acid stability.
- To compare the ribosomal binding affinity and in vitro/in vivo potency of telithromycin against macrolides, especially in resistant strains.
Main Methods:
- Structural analysis of telithromycin, highlighting modifications at C3 (keto function) and C6 (methoxy group).
- Investigation of the carbamate extension at C11/C12 and its impact on target binding.
- In vitro experiments measuring ribosomal binding affinity of telithromycin compared to erythromycin A and clarithromycin against wild-type and resistant strains.
Main Results:
- Telithromycin's keto function at C3 circumvents MLS(B) inducible resistance.
- Methoxy group at C6 enhances acid stability, crucial for oral administration.
- Telithromycin exhibits significantly higher affinity for both wild-type and MLS(B)-resistant ribosomes compared to erythromycin A and clarithromycin.
- Superior potency of telithromycin against Gram-positive cocci in vitro and in vivo correlates with increased ribosomal binding.
Conclusions:
- Telithromycin represents a significant advancement in combating macrolide-resistant respiratory pathogens.
- Its unique structural features provide enhanced ribosomal binding and broad-spectrum activity, including against resistant strains.
- Telithromycin offers a valuable therapeutic option for respiratory tract infections where macrolide resistance is a concern.