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New macrolides active against Streptococcus pyogenes with inducible or constitutive type of
P B Fernandes1, W R Baker, L A Freiberg
1Anti-Infective Research, Abbott Laboratories, Abbott Park, Illinois 60064.
Abstract:
Macrolide-resistant bacteria can be classified as inducibly resistant or constitutively resistant. Inducibly resistant bacteria are resistant to 14-membered macrolides, such as erythromycin and clarithromycin (A-56268), but are susceptible to the 16-membered macrolides, such as tylosin and spiramycin, as well as to clindamycin. Constitutively resistant bacteria are resistant to macrolide-lincosamide-streptogramin B antibiotics. In this study, the MICs of several erythromycin and clarithromycin analogs against macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains were determined. Four 11,12-carbamate analogs of clarithromycin had lower MICs than erythromycin did against S. pyogenes with the inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance. Five 11,12-carbonate analogs of erythromycin with modifications at the 4" position of cladinose had lower MICs than did erythromycin against S. pyogenes with the constitutive type of resistance, and one of these compounds, which had a naphthyl-glycyl substitution at the 4" position, had a lower MIC than erythromycin against both the inducibly resistant and constitutively resistant strains. Two analogs of erythromycin with a modification on the 4" position of cladinose had lower MICs than erythromycin did against the constitutively resistant organisms but not against the inducibly resistant organisms. Thus, 14-membered macrolides can be modified so as to confer a low MIC when tested in vitro.
Insights
Novel 14-membered macrolide analogs show reduced activity against resistant Streptococcus pyogenes strains. Modifications to erythromycin and clarithromycin offer potential for overcoming macrolide resistance in bacteria.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Bacteriology
Background:
- Macrolide resistance in bacteria is a growing concern, with two main types: inducible and constitutive.
- Inducible resistance affects susceptibility to 14-membered macrolides but not 16-membered ones or clindamycin.
- Constitutive resistance confers resistance to macrolide-lincosamide-streptogramin B (MLSB) antibiotics.
Purpose of the Study:
- To evaluate the in vitro activity of novel erythromycin and clarithromycin analogs against macrolide-resistant Streptococcus pyogenes.
- To determine if structural modifications can overcome inducible and constitutive macrolide resistance mechanisms.
Main Methods:
- Determination of minimum inhibitory concentrations (MICs) for various macrolide analogs.
- Testing against both macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains (inducible and constitutive resistance).
Main Results:
- Four clarithromycin carbamate analogs showed lower MICs than erythromycin against both inducible and constitutive resistant S. pyogenes.
- Five erythromycin carbonate analogs with 4" cladinose modifications exhibited lower MICs against constitutively resistant strains.
- One specific analog with a naphthyl-glycyl substitution demonstrated reduced MICs against both resistance types.
Conclusions:
- Structural modifications of 14-membered macrolides can lead to compounds with lower MICs against resistant bacterial strains.
- These modified macrolides hold promise for combating macrolide resistance in Streptococcus pyogenes infections.