Species selectivity of new siderophore-drug conjugates that use specific iron uptake for entry into bacteria

Abstract

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 they were conjugated to carbacephalosporin, erythromycylamine, or nalidixic 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, Pasteurella haemolytica, Streptococcus suis, Staphylococcus aureus, and Staphylococcus epidermidis. In some species, the inhibitory activities of the drug conjugates were associated with the ability of the bacteria to use the siderophore portion of the molecules for growth promotion in disc diffusion tests (0.04 mumol of conjugate or siderophore per disc). E. coli used catechol-based siderophore portions as well as hydroxamate-based tri-delta-OH-N-OH-delta-N-acetyl-L-ornithine ferric iron ligands for growth under iron-restricted conditions achieved by supplemental ethylenediamine di (O-hydroxyphenylacetic acid) (100 micrograms/ml) and was sensitive to carbacephalosporin conjugated to these siderophore 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 activities of some conjugates seemed partly linked to their ability to withhold iron from these bacteria, since individual siderophore portions showed some antibacterial effects. Individual siderophores did not promote S. suis growth in restrictive conditions, but the type of ferric iron ligands attached to beta-lactams affected inhibitory activities. The antibacterial activities of the intracellular-acting agents erythromycylamine and nalidixic acid were reduced or lost, even against S. aureus and S. epidermidis, when the agents were conjugated to siderophores. Conjugate-resistant E. coli mutants showed the absence of some iron-regulated outer membrane proteins in gel electrophoresis profiles and in specific phage or colicin sensitivity tests, implying that the drugs used outer membrane receptors of ferric complexes to get into cells.

Siderophore–fluoroquinolone conjugates containing potential reduction-triggered linkers for drug release: synthesis and antibacterial activity

“…The results therefore suggest that the “trimethyl lock” facilitated drug release process occurred after the conjugate was transported. Also notable is that mixed-ligand conjugates 23 and 25 showed a narrower spectrum of activity (Gram-negative) relative to the desferrioxamine conjugates, which is consistent with previous observations and suggests bacterial outer membrane recognition selectivity as expected (Diarra et al 1996; Ghosh et al 1996; Wencewicz and Miller 2013). Although the anticipated drug release process might happen, all four conjugates are less active relative to the parent drug ciprofloxacin.…”

“…Desferrioxamine B, a hydroxamate-containing siderophore, is utilized by a variety of Gram-positive and Gram-negative bacteria and some fungi (Müller and Raymond 1984). The artificial mixed-ligand siderophore containing both catecholate and hydroxamate ligands was designed to use multiple siderophore recognition processes to initiate active transport through the outer membrane of various Gram-negative species (Diarra et al 1996; Ghosh et al 1996; Wencewicz and Miller 2013). The drug linked to the siderophores was ciprofloxacin, a broad-spectrum fluoroquinolone antibiotic that targets bacterial DNA gyrases and topoisomerases (Mitscher 2005).…”

Characterization of ‘Schizokinen’; a dihydroxamate-type siderophore produced by Rhizobium leguminosarum IARI 917

“…SDS PAGE analysis of these cell fractions (Figure 7) clearly indicated the expression of an OM protein under low iron conditions both in the cell and OM pellet. This protein has a MW of approximately 74 kDa, which is similar to the molecular weight of OM receptor proteins previously reported in other bacteria (Reigh & O'Connell 1993;Diarra et al 1996). Vicibactin, a trihydroxamate siderophore (Figure 1a) produced by R. leguminosarum strain 8401 (pRL1JI), is thought to be transported by a fhuA homolog (Stevens et al 1999;Yeoman et al 2000).…”

“…Rhizobactin 1021, a common rhizobial siderophore, differs from schizokinen only in that it contains a lipid moiety attached to it that may facilitate the formation of micelles, protecting it from extracellular damage (Persmark et al 1993, Johnston 2004). An iron-repressible OM protein of 74 kDa has also been detected, which falls within the reported range for molecular weights of known ferric -siderophore OM receptor proteins (Reigh and O'Connell 1993;Diarra et al 1996). …”

'Think like a bacterium': a helpful concept to prolong the antibiotic era?

“…Without prompt and specific antiviral treatment, the disease is associated with mortality rates exceeding 70% and equally high rates of severe morbidity in those who survive the acute infection [1,2]. Two major clinical trials [3,4] demonstrated that the antiviral drug acyclovir, if given early in the course of the disease, dramatically reduced both the mortality and morbidity of the dsease. HSE typically presents as an acute neurologic disease associated with an initial prodrome of fever, headache and nausea.…”