Synthesis and Activities of Pyoverdin−Quinolone Adducts: A Prospective Approach to a Specific Therapy Against Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is particularly resistant to most all the antibiotics presently available, essentially because of the very low permeability of its outer membrane. To overcome this, we synthesized four siderophore-based antibiotics formed by two quinolones - norfloxacin and benzonaphthyridone - bound to the pyoverdin of P. aeruginosa ATCC 15692 via two types of spacer arms: one stable and the other readily hydrolyzable. From the comparison of their antibacterial properties with those of the two unbound quinolones, we reached the following conclusions: (a) The adducts inhibit Escherichia coli's gyrase showing that the dissociation of the compounds is not necessary for their activity. However, the presence of the pyoverdin moiety on the molecule decreases the inhibition activity compared to the antibiotic alone. (b) They facilitate the uptake of (55)Fe using the specific pyoverdin-mediated iron-transport system of the bacterium. No uptake was observed either with P. aeruginosa ATCC 27853, which produces a structurally different pyoverdin, or with P. aeruginosa K690, which is a mutant of P. aeruginosa ATCC 15692 lacking FpvA, the outer-membrane pyoverdin receptor. (c) MIC determinations have shown that only strains P. aeruginosa ATCC 15692 and the derived outer-membrane receptor-producing but pyoverdin-deficient P. aeruginosa IA1 mutant present higher susceptibility to the pyoverdin-quinolone adducts, whereas P. aeruginosa ATCC 27853 and K690 are much more resistant. (d) Growth inhibition by these adducts confirmed these results and showed that the adducts with the hydrolyzable spacer arm have better activity than those with the stable one and that the labile spacer arm adducts present much higher activity than the quinolones alone. These results show clearly that the penetration of the antibiotic into the cells is favored when this latter is coupled with pyoverdin: Only the strains possessing the appropriate outer-membrane receptor present higher susceptibility to the adduct. In this case the antibiotic uses the pyoverdin-mediated iron-transport system. Furthermore, better efficiency is obtained when the spacer arm is labile and favors the antibiotic release inside the cell, allowing better inhibition of gyrase.

Binding Properties of Pyochelin and Structurally Related Molecules to FptA of Pseudomonas aeruginosa

“…Also, as iron is essential for these pathogenic organisms, FptA could be a promising target for new antibiotic design or could be used, for example, to transport antibiotics into the cells using a Trojan horse strategy. [38][39][40] The development of such strategies requires knowledge of the recognition mechanism by FptA of Pch and ferric-Pch and a better understanding of the structure-activity relationships between Pch analogues and FptA. Therefore, we have investigated the binding and iron uptake properties of FptA with the four diastereoisomers of synthetic Pch, with other Pch Figure 1.…”

FvtA Is the Receptor for the Siderophore Vanchrobactin inVibrio anguillarum: Utility as a Route of Entry for Vanchrobactin Analogues

“…The vanchrobactin chemical structure was recently determined, and a series of vanchrobactin analogues which have functionality (an amino group) appropriate for use as antibiotic vectors and keep their siderophore activity have been synthesized and evaluated (36,37). Similar approaches have been used and have provided promising results with the pyoverdine-mediated iron uptake system (18) and conjugated siderophore-␤-lactamase inhibitors (9).…”

Role of siderophores in cystic fibrosis pathogenesis: Foes or friends?

“…In a similar way, pyoverdine-fluoroquinolone conjugates showed promising bactericidal activity (Hennard et al, 2001). Only P. aeruginosa strains, producing the same pyoverdine type used to attach fluoroquinolones, demonstrated enhanced susceptibility (Hennard et al, 2001). Recently, different pyochelin-norfloxacin conjugates were tested against P. aeruginosa.…”