Chapter 19 : Ketolides

Abstract:

The ketolides belong to group IIC of the classification of macrolides. All ketolides are characterized structurally by the absence of an α-L-cladinose at position 3 of the erythronolide A and the presence of a 3-keto group. The affinity for ribosomes is higher for ketolides than for erythromycin A. The dissociation constants are summarized. Cethromycin binds tightly to ribosomes in comparison to erythromycin A. Blockade of the exit tunnel by ketolides induces premature dissociation of peptidyl-tRNAs from the ribosome. The available ketolides inhibit the assembly of 50S sub-units of Staphylococcus aureus and Streptococcus pneumoniae. Various ketolides have been shown not to be capable of inducing resistance to other macrolides. This phenomenon has been explored with strains of S. aureus, S. pneumoniae, and Streptococcus pyogenes in the presence of ketolides and their counterpart with an L-cladinose and with clarithromycin, erythromycin A, and azithromycin. Erythromycin A accumulation dropped about 70 to 80% after erm induction. Ketolides could accumulate in the bacterial cell to preinduction level, and the concentration remains high enough to interfere with the ribosome. The efflux mechanism of resistance of S. pneumoniae involves a Mef protein, which binds to macrolides and ketolides and extrudes them from the bacterial cell, resulting in reduced intracellular drug concentrations. The ability of sequential subcultures in subinhibitory concentrations of telithromycin, azithromycin, roxithromycin, clindamycin, and pristinamycin to select for resistance was investigated. Introduction of halogen at the C-2 position of the erythronolide A ring leads to the synthesis of HMR 3562 and HMR 3787.