Mechanisms of action of cephalosporin 3'-quinolone esters, carbamates, and tertiary amines in Escherichia coli

Antimicrob Agents Chemother. 1993 Mar;37(3):559-65. doi: 10.1128/AAC.37.3.559.

Abstract

Cephalosporin 3'-quinolone esters, carbamates, and tertiary amines are potent antibiotics whose antibacterial activities reflect the action of both the beta-lactam and the quinolone components. The biological properties of representative compounds from each class were compared in Escherichia coli. All compounds bound to the essential PBP 3, inhibited DNA gyrase, and caused filamentation in growing cells. To distinguish between cephalosporin- and quinolone-induced filaments, nucleoid segregation was also examined, as quinolones disrupt nucleoid segregation while the beta-lactams do not (N. H. Georgopapadakou and A. Bertasso, Antimicrob. Agents Chemother. 35:2645-2648, 1991). The cephalosporin quinolone esters Ro 23-9424 and Ro 24-6392, at concentrations causing filamentation in E. coli ATCC 25922, did not affect nucleoid segregation after 1 h of incubation (cephalosporin response) but did not affect it after 2 h (quinolone response), indicating the release of free quinolone. Accordingly, only the quinolone response was produced in a strain possessing TEM-3, an expanded-spectrum beta-lactamase. The cephalosporin carbamate Ro 24-4383 and the tertiary amine Ro 24-8138 produced a quinolone response in E. coli ATCC 25922, though they produced a cephalosporin response in a quinolone-resistant strain. Carbamate and tertiary amine linkages are chemically more stable than the ester linkage, and both cephalosporin 3'-quinolone carbamates and tertiary amines are more potent inhibitors of DNA gyrase than are the corresponding esters. The results suggest that, while intact cephalosporin 3'-quinolone esters act as cephalosporins, carbamates and amines may possess both cephalosporin and quinolone activity in the intact molecule.

MeSH terms

  • Amines / pharmacology
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacokinetics
  • Anti-Infective Agents / pharmacology*
  • Bacterial Proteins*
  • Carrier Proteins / metabolism
  • Cefotaxime / chemistry
  • Cefotaxime / pharmacokinetics
  • Cefotaxime / pharmacology
  • Ceftriaxone / chemistry
  • Ceftriaxone / pharmacokinetics
  • Ceftriaxone / pharmacology
  • Cell Nucleus / drug effects
  • Cephalosporins / chemistry
  • Cephalosporins / pharmacokinetics
  • Cephalosporins / pharmacology*
  • Ciprofloxacin / chemistry
  • Ciprofloxacin / pharmacokinetics
  • Ciprofloxacin / pharmacology
  • Escherichia coli / drug effects*
  • Escherichia coli / growth & development
  • Hexosyltransferases*
  • Muramoylpentapeptide Carboxypeptidase / metabolism
  • Penicillin-Binding Proteins
  • Peptidyl Transferases*
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors

Substances

  • Amines
  • Anti-Infective Agents
  • Bacterial Proteins
  • Carrier Proteins
  • Cephalosporins
  • Penicillin-Binding Proteins
  • Topoisomerase II Inhibitors
  • Ciprofloxacin
  • Ceftriaxone
  • Peptidyl Transferases
  • Hexosyltransferases
  • Muramoylpentapeptide Carboxypeptidase
  • Cefotaxime