Macrolones – novel class of macrolide antibiotics active against key resistant respiratory pathogens

Background: As incidence of infections caused by bacteria resistant to one or more antibiotic classes increases, there is a constant need for development of new, more effective and safe antimicrobial drugs. Macrolones are a novel class of antibacterial macrolide compounds, characterized by a quinolone moiety attached via linker by an ester bond to 4’’ position of macrolide scaffold. Methods: Antibacterial activity of macrolones against key respiratory pathogens was determined and their pharmacodynamics assessed using time- kill methodology. Macromolecular synthesis and TnT assay were used to test mechanism of action. In vitro resistance development potential was determined by measuring spontaneous mutation rates and by passage studies in sub-inhibitory concentrations of compounds. In vivo efficacy was tested in murine pneumonia model. Results: Macrolone spectrum of activity comprises key bacterial respiratory pathogens with in vitro profiles superior to those of marketed macrolide antibiotics and ketolide telithromycin, including macrolide resistant S. pneumoniae, S. pyogenes and S. aureus strains (overall more than 250 clinical isolates tested). Representative macrolone compound exhibits MIC90 values against MLSb S. pneumoniae and H. influenzae comparable to telithromycin, while superior against iMLSb and cMLSb strains of S.pyogenes (MIC90 <0.015 vs. 4 mg/L and 0.5 vs. 32 mg/L, respectively). Unlike macrolides and ketolides, macrolones showed rapid bactericidal effect against H. influenzae. Their activity at ribosomal level was confirmed by macromolecular synthesis and TnT assays. Macrolones exhibited equal or lower in vitro resistance development potential than azithromycin and telithromycin in S. pneumoniae, while in H.influenzae mutants were not detected. In S. pneumoniae mutations were found in gene for ribosomal protein L22. The efficacy observed in vitro was confirmed in murine pneumonia model induced by both eryS and eryR S. pneumoniae. Conclusion: The results obtained clearly demonstrate superior activity of maclones vs. marketed macrolides and ketolides.