ABSTRACT
Glycopeptides whose aminosugars have been modified by attachment of hydrophobic side chains are frequently active against vancomycin-resistant microorganisms. We have compared the conformations of six such fluorinated glycopeptides (with side chains of varying length) complexed to cell walls labeled with d-[1-(13)C]alanine, [1-(13)C]glycine, and l-[ε-(15)N]lysine in whole cells of Staphylococcus aureus. The internuclear distances from (19)F of the bound drug to the (13)C and (15)N labels of the peptidoglycan, and to the natural abundance (31)P of lipid membranes and teichoic acids, were determined by rotational-echo double resonance NMR. The drugs did not dimerize, and their side chains did not form membrane anchors but instead became essential parts of secondary binding to pentaglycyl bridge segments of the cell-wall peptidoglycan.
Subject(s)
Glycopeptides/chemistry , Glycopeptides/metabolism , Peptidoglycan/chemistry , Staphylococcus aureus/metabolism , Alanine/genetics , Binding Sites , Cell Membrane/metabolism , Glycine/genetics , Hydrophobic and Hydrophilic Interactions , Lysine/genetics , Nuclear Magnetic Resonance, Biomolecular , Peptidoglycan/metabolismSubject(s)
Anti-Bacterial Agents/chemistry , Osteomyelitis/drug therapy , Prodrugs/chemistry , Rifamycins/chemistry , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemical synthesis , Osteomyelitis/prevention & control , Prodrugs/administration & dosage , Prodrugs/chemical synthesis , Rats , Rifamycins/administration & dosage , Rifamycins/chemical synthesis , Staphylococcus aureus/drug effectsABSTRACT
Osteomyelitis is a difficult to treat bacterial infection of the bone. Delivering antibacterial agents to the bone may overcome the difficulties in treating this illness by effectively concentrating the antibiotic at the site of infection and by limiting the toxicity that may result from systemic exposure to the large doses conventionally used. Using bisphosphonates as osteophilic functional groups, different forms of fluoroquinolone esters were synthesized and evaluated for their ability to bind bone and to release the parent antibacterial agent. Bisphosphonated glycolamide fluoroquinolone esters were found to present a profile consistent with effective and rapid bone binding and efficient release of the active drug moiety. They were assessed for their ability to prevent bone infection in vivo and were found to be effective when the free fluoroquinolones were not.
Subject(s)
Esters/chemical synthesis , Esters/pharmacology , Fluoroquinolones/chemistry , Organophosphonates/chemistry , Osteomyelitis/prevention & control , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Animals , Disease Models, Animal , Esters/chemistry , Female , Humans , Molecular Structure , Prodrugs/chemistry , RatsABSTRACT
Since its inception, ketene chemistry has developed into a unique and well-established source of useful transformations for conventional synthetic organic chemistry. It is, therefore, not surprising that soon after their movement from the realm of peptide and peptoid libraries to that of small molecules, combinatorial chemists have sought the benefits of ketene chemistry to satisfy their own synthetic needs. The ability of these versatile molecules to undergo reactions with nucleophiles, and to participate in cycloadditions and cyclocondensations, has been utilized for the preparation of diverse heterocyclic compounds, and has added to the advantages of polymer-assisted synthesis for rapid purification. Different types of ketenes and different methods for their generation have been involved, which illustrates the potential diversity of the chemistry. There is now a better grasp of the effect of the fragility of these sometimes transient molecules on the reactions involving solid supports, and this augurs well for the application of some of the more recent developments in ketene chemistry to the generation of small-molecule libraries.
