The design, synthesis and study of siderophore-antibiotic conjugates. Siderophore mediated drug transport

Biol Met. 1991;4(1):62-9. doi: 10.1007/BF01135559.

Abstract

The use of conjugates of microbial iron chelators (siderophores) and antibiotics for illicit transport of antibiotics into cells is a potentially powerful method for the rational design of therapeutic agents. The structural complexity of most natural siderophores has impeded progress in this area. Described here are the design, syntheses and preliminary biological studies of several siderophore-beta-lactam antibiotic conjugates. Both hydroxamic-acid-based and catechol-based conjugates with and without amino acid spacers to carbacephalosporins were synthesized and demonstrated to be effective inhibitors of Escherichia coli X580. Mutant selection was noted for each class of conjugates. Mutants selected from exposure of the E. coli to the hydroxamate conjugates were susceptible to the catechol conjugates and vice versa. Combinations of hydroxamate- and catechol-carbacephalosporin conjugates were most effective inhibitors of E. coli X580.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology
  • Biological Transport, Active / drug effects
  • Cephalosporins / chemical synthesis
  • Cephalosporins / pharmacokinetics
  • Cephalosporins / pharmacology
  • Drug Design
  • Escherichia coli / drug effects
  • Ferrichrome / analogs & derivatives
  • Ferrichrome / chemical synthesis
  • Ferrichrome / chemistry
  • Iron Chelating Agents / chemical synthesis*
  • Iron Chelating Agents / chemistry
  • Iron Chelating Agents / pharmacology
  • Molecular Structure
  • Siderophores

Substances

  • Anti-Bacterial Agents
  • Cephalosporins
  • Iron Chelating Agents
  • Siderophores
  • carbacephems
  • Ferrichrome
  • albomycin