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Category: Bacterial Pathogenesis
Ketolides, Page 1 of 2
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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.
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Classification of 14- and 15-membered-ring macrolides
Modifications of erythromycin A by semisynthesis
Definition of a ketolide
Picromycin and narbomycin
In vitro activity of narbomycin
9-Oxime-3-keto-erythromycin A derivative (Le Mahieu et al., 1974)
Hemiketalization between C-6 hydroxyl and 3-keto
Acid stability of ketolides
11,12-Carbamate and C-6-O-alkyl derivative
RU-504 (9-oxime ketolide)
Carbamate derivatives of clarithromycin
Derivatives of the 11,12, cyclic 9-amine ketolide type
Carbamate and carbazate ketolides
HMR 3004
9-Oxime piperidyl carbamate ketolide
Stability of roxithromycin in an acidic medium (pH 4.2) (Bryskier et al., 1993)
Stability of HMR 3004 in an acidic medium
Telithromycin
Ketolides: experimental induction (S. aureus) ( Bonnefoy et al., 1997 )
Ketolides: experimental induction (S. pyogenes) ( Bonnefoy et al., 1997 )
Telithromycin: correlation between efficacy and pharmacokinetic or pharmacodynamic parameters ( Vesga et al., 1997 )
Cellular/extracellular ratio of telithromycin in human granulocytes (Labro et al., 1997, 1998)
Telithromycin efflux (Labro et al., 1998)
Metabolites from telithromycin
Cethromycin (ABT-773)
TE-810
Tricyclic ketolides: monosubstitution on the imine nucleus
3-Acyl erythromycin A
Carbamate macrolides
HMR 3787 and HMR 3562
Bridged bicyclic ketolides
O -Arylpropargyl-9-oxime-2-fluoro-carbamate ketolide
6-O-Heteroaryl propenyl ketolides
HMR 3832
EP-13420
9-Oxime-2 substituted ketolides
13-Modified substituted ketolides
15-Amido ketolides
GW 773546 and GW 708408
Lactone ketolides
JNJ 17069546
A-217213
Bifunctional ketolides
FMA 0713
A-179796 and A-179797
3-Deoxyclarithromycin
Tylosin and aza-ketolide analogs
EP-263, EP-935, and EP-1126
In vitro activity of descladinose clarithromycin
In vitro activities of the carbamate derivatives of clarithromycin
In vitro activity of RU-57708 versus A-66321 a
Activities of carbamate ketolides against S. pyogenes and S. pneumoniae resistant to erythromycin A by efflux
In vitro activity of HMR 3004 a
Telithromycin and HMR 3004: physicochemical properties
Telithromycin: in vitro activity against S. aureus
Telithromycin: activity against S. pyogenes a
Telithromycin: in vitro activity against S. pneumoniae
Activity of telithromycin against viridans group streptococci
Telithromycin: in vitro activity against gram-positive bacilli
In vitro activity of telithromycin against erythromycin A-resistant coryneforms (MIC, >0.5 μg/ml)
Activity of telithromycin against E. faecalis a
Activity of telithromycin against E. faecium a
Activities of telithromycin and 14- and 15-membered-ring macrolides against B. pertussis a
Activities of macrolides against C. pneumoniae a
Activities of macrolides against L. pneumophila a
In vitro activities of antibacterials against Parachlamydia
Activities of antibacterials against T. whipplei
In vitro activities of antibacterials against Afipia and Bosea
Telithromycin: activity against bacteria responsible for sexually transmitted diseasesa
Telithromycin: in vitro activity against anaerobic bacteria
Telithromycin: in vivo activity against B. fragilis a
Telithromycin activity against bacteria responsible for infections due to animal bites a
ED100 in the prevention of acute toxoplasmosis a
Affinity of ketolides for ribosomes
Dissociation constants
HMR 3004: resistance by efflux
Pentapeptide sequences from K-peptides
Mechanisms of inactivation of macrolides a
Telithromycin: dosage frequency a
Pharmacokinetics of telithromycin administered orally (repeated doses)
Lung distribution of telithromycin
Telithromycin pharmacokinetics in elderly subjects
Telithromycin pharmacokinetics in hepatically impaired patients after a single oral dose of 800 mg
Pharmacokinetics of telithromycin in hepatically impaired patients after repeated 800-mg doses a
Telithromycin pharmacokinetics in renally impaired patients after a single oral dose of 800 mg
In vitro activities of telithromycin metabolites
Elimination of telithromycin and its main metabolites
Pharmacokinetics of telithromycin after ascending doses a
Pharmacokinetics of RU-76363
Telithromycin concentration in middle ear fluid
Pharmacokinetics of HMR 3004 and telithromycin in humans after 600 mg (oral)
Pharmacokinetics after ascending oral doses of HMR 3004
Pharmacokinetics of TE-810 in animals after a dose of 5 mg/kg orally
In vitro activity of compound I
In vitro activity of EP-13159
Pharmacokinetics of ketolides in mice after administration of 25 mg/kg (oral doses)
In vitro activities of JNJ 17156581 and JNJ 17156815
In vitro activity of HMR 3832 against gram-positive bacteria
Antipneumococcal and anti-H. influenzae activities of GW 773546 and GW 708408
In vitro activity of A-217213 a
In vitro activity of FMA 0713
In vitro activity of A-179796