SPECIES SELECTIVITY OF NEW SIDEROPHORE-DRUG CONJUGATES THAT USE SPECIFIC IRON UPTAKE FOR ENTRY INTO BACTERIA

Siderophores selectively bind ferric iron and are involved in receptor -specific iron transport into bacteria. Several types of siderophores were synthesized, and growth-promoting or inhibitory activities when t hey were conjugated to carbacephalosporin, erythromycylamine, or nalid ixic acid were investigated, Overall, 11 types of siderophores and 21 drug conjugates were tested against seven different bacterial species: Escherichia coli, Bordetella bronchiseptica, Pasteurella multocida, P asteurella haemolytica, Streptococcus suis, Staphylococcus aureus, and Staphylococcus epidermidis, In some species, the inhibitory activitie s of the drug conjugates were associated with the ability of the bacte ria to use the siderophore portion of the molecules for growth promoti on in disc diffusion tests (0.04 mu mol of conjugate or siderophore pe r disc), E. coli used catechol-based siderophore portions as well as h ydroxamate-based tri-delta-OH-N-OH-delta-N-acetyl-L-ornithine ferric i ron ligands for growth under iron-restricted conditions achieved by su pplemental ethylenediamine di(O-hydroxyphenylacetic acid) (100 mu g/ml ) and was sensitive to carbacephalosporin conjugated to these sideroph ore types (up to a 34-mm-diameter inhibition zone), B. bronchiseptica used desferrioxamine B and an isocyanurate-based or trihydroxamate in addition to catechol-based siderophore portions for promotion but was not inhibited by beta-lactam conjugates partly because of the presence of beta-lactamase. P. multocida and P. haemolytica did not use any of the synthetic siderophores for growth promotion, and the inhibitory a ctivities of some conjugates seemed partly linked to their ability to with-hold iron from these bacteria, since individual siderophore porti ons showed some antibacterial effects. Individual siderophores did not promote S. suis growth in restrictive conditions, but the type of fer ric iron ligands attached to beta-lactams affected inhibitory activiti es, The antibacterial activities of the intracellular-acting agents er ythromycylamine and nalidixic acid were reduced or lost, even against S. aureus and S. epidermidis, when the agents were conjugated to sider ophores, Conjugate-resistant E. coli mutants showed the absence of som e iron-regulated outer membrane proteins in gel electrophoresis profil es and in specific phage or colicin sensitivity tests, implying that t he drugs used outer membrane receptors of ferric complexes to get into cells.