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Category: Bacterial Pathogenesis
Codrugs, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815929/9781555812379_Chap28-1.gif /docserver/preview/fulltext/10.1128/9781555815929/9781555812379_Chap28-2.gifAbstract:
The majority of codrugs studied possess either a cephalosporin, a penem, or a carbapenem. Studies of the mechanisms of action of codrugs have been conducted principally with Ro-23-9424, Ro-24-4384 (carbamate), and Ro-24-8138 (tertiary amine). The activity of the fluoroquinolones is evaluated in vitro in terms of the inhibition of DNA gyrase activity and in vivo in the bacterium in terms of its action on the nucleoid (topoisomerase IV) using 4’,6’-diamidino-2-phenylindole. Studies have been conducted on E. coli TE-18, which is a strain derived from E. coli K-12. The selection of fleroxacin-resistant mutants from this strain is greater than that observed with fleroxacin alone or from another strain, such as E. coli JF 568. The 3’-esters are much less chemically stable than the other derivatives. The first molecule in which a cephalosporin and a quinolone were combined was Ro-23-5068. The most widely studied molecule has been Ro-23-9424, but Ro-24-6392 has also been widely studied in vitro and in terms of the mechanism of action. Ro-25-0534 is a combination of a catechol-type cephalosporin and ciprofloxacin, linked by a tertiary amine bond. This molecule is active against strains of Enterobacteriaceae which are cefotaxime resistant as a result of cephalosporinase production. Combinations of penems and fluoroquinolones have been synthesized with the various bonds described for the cephalosporins. The chapter also talks about carbapenems-fluoroquinolones, penicillins-Quinolones, monocyclic β-lactams/quinolones, and oxazolidinones-quinolones.
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Release of the compound at C-3’ of the cephem nucleus
Cephem: C-3’-omidine derivative mercaptopyridine-N-oxide (MCO)
Haloalanyl cephalosporin
Classification of combined molecules
β-Lactam–fluoroquinolone bond
Structures of cefotaxime, Ro-23-9424, desacetylcefotaxime, and fleroxacin
CQ-414 and CQ-397
Mechanism of action of β-lactams–fluoroquinolones (adapted from Dax et al., 1993)
Carbamate derivatives
Ro-23-5068
Ro-24-6392
Oral codrugs
PD-147767 and PD-152915
Quinolonylcephem secondary amines
Ro-25-0534
Thioester derivative of Ro-23-9424
Quaternary ammonium codrugs
PGE-8335534
Penem-quinolone codrugs
Ro-25-0695
Procter & Gamble molecules (1993)
Carbapenems synthesized by Hoffmann-La Roche
Penicillin-norfloxacin codrugs
Monobactam-quinolone
MCB 116, MCB 2038, and MCB 1033
In vitro activity of mercaptopyridine-N-oxide
Activity of the omidine nucleus against β-lactamase-producing strains
Affinities of β-lactams for S. aureus ATCC 25923 PBP
Activities of codrugs against DNA
Degradation half-lives of Ro-23-9424 according to the biological medium
Degradation half-lives of codrugs
Activity of Ro-23-9424 against gram-negative bacilli
In vitro activity of Ro-23-9424 against cephalosporinase-producing Enterobacteriaceae
In vitro activity of Ro-23-9424 against S. pneumoniae
In vitro activity of Ro-23-9424 against gram positive bacteria
Selection of mutants of Ro-23-9424
Plasma pharmacokinetics of Ro-23-9424 (20 mg/kg intravenously) in animals
Plasma pharmacokinetics of Ro-23-9424 in humans
In vivo activity of Ro-24-4383
Plasma pharmacokinetics kinetics of PD-152915 and PD-147767 orally (50 mg/kg) in the rat
In vitro activities of CQ-397 and CQ-414
In vitro activities of penem-quinolone codrugs
Affinities of penem-quinolone prodrugs for S. aureus ATCC 29213 PBP
Plasma pharmacokinetics (20 mg/kg intravenously) of PGE-4924490
In vitro activities of carbapenem-quinolone codrugs
Antibacterial activities of oxazolidinones-quinolones