Ketolides: novel antibacterial agents designed to overcome resistance to erythromycin A within gram-positive cocci

Macrolide Antibiotics

“…Initial in vitro testing of a group of natural product antibiotics confirmed the earlier observation that 3-keto macrolides did not induce MLS B resistance and they did inhibit inducible erm-resistant staphylococci and streptococci (50,51). Taking these results as a lead for additional investigation (50)(51)(52)(53), researchers at Roussel-Uclaf (now Sanofi) further demonstrated that removal of cladinose and then oxidation to the 3-ketone in erythromycin did produce such active compounds (54), especially if additional substituents for stronger ribosomal binding were added at other sites in the structures (55). In a fortunate circumstance of timing, the specter of pan-microbial resistance was rising and desperate calls for new antibiotics were becoming increasingly frequent, which publicized the need and urgency for developing new antibiotics such as the ketolides (56)(57)(58).…”

Pharmacodynamic Profile of Telithromycin against Macrolide- and Fluoroquinolone-Resistant Streptococcus pneumoniae in a Neutropenic Mouse Thigh Model

“…As a result, while the pharmacodynamic parameter most predictive of outcome (i.e., AUC/MIC) remains constant in the absence or the presence of neutrophils, the magnitude of drug exposure required to produce any given reduction in bacterial density is substantially reduced in the immunocompetent host. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]1998) evaluated the impacts of neutrophils on the bacteriostatic activity of telithromycin and a structurally related ketolide against S. pneumoniae strains with various macrolide susceptibilities in the murine thigh infection model and reported that the potencies of the ketolides are enhanced (1.8-to 24-fold) in the presence of neutrophils. Moreover, although neutropenic conditions were used in the present study, the enhanced in vivo potency of another ketolide, ABT-773, against pneumococci in immunocompetent hosts has also recently been demonstrated (5).…”

“…Telithromycin is a semisynthetic derivative of the 14-membered-ring macrolide parent compound erythromycin A. As a consequence of chemical modifications made to the parent compound, telithromycin is highly acid stable, has an extended half-life, and lacks the ability to induce resistance to other macrolides (4). Additionally, these alterations allow telithromycin to retain activity against macrolide-resistant isolates due to the presence of the mefA and/or the ermB gene and against S. pneumoniae strains with 23S rRNA mutations (4,14).…”

“…As a consequence of chemical modifications made to the parent compound, telithromycin is highly acid stable, has an extended half-life, and lacks the ability to induce resistance to other macrolides (4). Additionally, these alterations allow telithromycin to retain activity against macrolide-resistant isolates due to the presence of the mefA and/or the ermB gene and against S. pneumoniae strains with 23S rRNA mutations (4,14). Typical telithromycin MICs at which 90% of isolates are inhibited (MIC 90 ) for S. pneumoniae range from 0.125 to 0.5 g/ml for both susceptible and penicillinand/or macrolide-resistant S. pneumoniae isolates (1,7,11,22).…”

Designer drugs for discerning bugs

“…The Deinococcus and Haloarcula structures proposed different conformations for the lactone ring of erythromycin and related macrolides (14,16); the orientation of part of clindamycin (a lincosamide) was flipped by 180°, as was the entire chloramphenicol molecule, compared with an analogous inhibitor anisomycin. Furthermore, the crystallographic models disagreed, not only with each other but also with genetic and biochemical data (17), over the position of a pair of heterocyclic (imidazolo-pyridyl) substituents that had been added to erythromycin to form its latest clinically approved derivative, telithromycin (18). The question on all ribosomologists' lips was as follows: were these discrepancies caused by fundamental species differences in the ribosomes or problems with the resolution and interpretation of the data?…”