Synthesis and activities of pyoverdin-quinolone adducts: A prospective approach to a specific therapy against Pseudomonas aeruginosa

Pseudomonas aeruginosa is particularly resistant to most all the antibiotic s 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 space r 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 necess ary for their activity. However, the presence of the pyoverdin moiety on th e molecule decreases the inhibition activity compared to the antibiotic alo ne. (b) They facilitate the uptake of Fe-55 using the specific pyoverdin-me diated iron-transport system of the bacterium. No uptake was observed eithe r with II? aeruginosa ATCC 27853, which produces a structurally different p yoverdin, or with P. aeruginosa K690, which is a mutant of P. aeruginosa AT CC 15692 lacking FpvA, the outer-membrane pyoverdin receptor. (c) MIC deter minations have shown that only strains P. aeruginosa ATCC 15692 and the der ived outer-membrane receptor-producing but pyoverdin-deficient P. aeruginos a IA1 mutant present higher susceptibility to the pyoverdin-quinolone adduc ts, 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 thos e with the stable one and that the labile spacer arm adducts present much h igher activity than the quinolones alone. These results show clearly that t he penetration of the antibiotic into the cells is favored when this latter is coupled with pyoverdin: Only the strains possessing the appropriate out er-membrane receptor present higher susceptibility to the adduct. In this c ase the antibiotic uses the pyoverdin-mediated iron-transport system. Furth ermore, better efficiency is obtained when the spacer arm is liabile and fa vors the antibiotic release inside the cell, allowing better inhibition of gyrase.