What are ketolides?
Ketolides are semi-synthetic derivatives of 14-membered macrolide antibiotics, like erythromycin. They were developed to provide enhanced activity against respiratory tract pathogens that have developed resistance to traditional macrolides. The defining chemical feature of ketolides is the replacement of the L-cladinose sugar at the C3 position of the erythronolide ring with a 3-keto group, giving the class its name. This modification, along with additional changes such as a carbamate extension at the C11/C12 positions in some agents, imparts unique pharmacological properties. Ketolides bind to the bacterial ribosome more avidly than macrolides, and their altered structure allows them to circumvent common resistance mechanisms. Telithromycin (marketed as Ketek) was the first and most prominent member of this class to receive regulatory approval.
Mechanism of action and resistance-overcoming properties
Like macrolides, ketolides inhibit bacterial protein synthesis by targeting the 50S ribosomal subunit. The critical difference lies in their binding affinity and location. Ketolides exhibit a dual-site binding mechanism, interacting with both domain II and domain V of the 23S rRNA on the ribosome. This two-point attachment provides a much tighter and more stable binding compared to macrolides, which primarily bind to one site.
This enhanced binding is particularly effective against bacteria that have developed resistance through two main mechanisms:
- Target site modification: The primary mechanism of macrolide resistance, known as MLSB resistance, is caused by erm genes that encode for methylase enzymes. These enzymes methylate a specific adenine base on the 23S rRNA, reducing macrolide binding. The unique structure of ketolides allows them to maintain high affinity for the ribosome even when this site is methylated, and importantly, they do not induce the expression of these resistance genes in strains where the methylation is inducible.
- Efflux pumps: Some bacteria, especially Gram-negative species, develop resistance by producing efflux pumps that actively expel macrolides from the bacterial cell. The structural modifications in ketolides, particularly the removal of the cladinose sugar, make them poor substrates for these efflux pumps.
Clinical uses and safety concerns
Telithromycin was initially approved for the treatment of community-acquired respiratory tract infections in adults, including community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis, and acute sinusitis. Its potent activity against multidrug-resistant Streptococcus pneumoniae and certain atypical pathogens made it a promising treatment option.
However, significant safety concerns emerged after its market release, leading to restrictions and eventual withdrawal for some indications. A prominent black-box warning was issued for telithromycin due to the risk of exacerbating myasthenia gravis, potentially leading to fatal respiratory failure. Additionally, cases of severe hepatotoxicity, including liver failure, were reported, casting a shadow over the entire class. Other side effects include gastrointestinal upset, dizziness, and visual disturbances, which are often transient. These issues largely curtailed the use of telithromycin and significantly impacted the development and commercialization of other ketolides, like cethromycin and solithromycin.
Ketolides versus macrolides: A comparison
While derived from macrolides, ketolides possess distinct features that were intended to improve upon the older class of antibiotics. The following table highlights the key differences and similarities:
| Feature | Macrolides (e.g., Erythromycin, Azithromycin) | Ketolides (e.g., Telithromycin) |
|---|---|---|
| Mechanism of Action | Bind primarily to domain V of 23S rRNA on the 50S ribosomal subunit. | Bind with high affinity to both domain II and domain V of 23S rRNA on the 50S ribosomal subunit. |
| Resistance Overcoming | Susceptible to resistance via erm gene-mediated methylation and efflux pumps. | Designed to overcome MLSB resistance and are poor substrates for many efflux pumps due to structural modifications. |
| Acid Stability | Erythromycin is acid-labile and less stable in the gastrointestinal tract. | Higher acid stability, allowing for more predictable oral bioavailability. |
| Adverse Effects | Generally well-tolerated, with gastrointestinal issues being most common. | Concerns over severe hepatotoxicity and exacerbation of myasthenia gravis, particularly with telithromycin. |
| Clinical Use | Broad use for a variety of respiratory, skin, and soft tissue infections. | Historically used for respiratory infections, but use is now limited due to severe safety concerns. |
| Structure | 14- or 15-membered lactone ring with L-cladinose sugar at the C3 position. | 14-membered lactone ring with a keto group at the C3 position and an aryl-alkyl chain attached elsewhere. |
The future of ketolides
Ketolides represent a notable effort to combat the growing issue of antibiotic resistance by modifying existing drug classes. Despite the promise of telithromycin's potent activity against resistant respiratory pathogens, its severe adverse effect profile significantly hampered the class's broader clinical adoption. The research community has not abandoned the concept entirely, and efforts to develop safer ketolide molecules have continued. While the clinical application of ketolides is limited in many regions, the pharmacological lessons learned from their development and use continue to inform the search for next-generation antibiotics. This ongoing research underscores the delicate balance between achieving therapeutic efficacy and ensuring patient safety in the face of evolving microbial threats.
Conclusion
In summary, ketolides are a subclass of semi-synthetic macrolide antibiotics developed to counteract common resistance mechanisms. Their unique mechanism of action, involving a dual-site binding to the bacterial ribosome, grants them enhanced potency against many resistant Gram-positive and atypical respiratory pathogens. However, the history of telithromycin, the most well-known ketolide, is a cautionary tale, illustrating how serious, rare adverse effects like hepatotoxicity and the exacerbation of myasthenia gravis can overshadow clinical promise. While their widespread use is limited today, ketolides demonstrate a successful strategy for designing antibiotics that overcome resistance, highlighting the importance of balancing therapeutic gains with rigorous safety evaluation. The future of this class depends on the development of new, safer molecules that can leverage their potent mechanism without the associated risks.
Full Article: The wobbly status of ketolides: where do we stand?
