The Synthesis and Antibacterial Activity of two Pyoverdin-ampicillin Conjugates, Entering Pseudomonas aeruginosa via the Pyoverdin-mediated Iron Uptake Pathway.

Abstract

Two pyoverdin-ampicillin conjugates were synthesized and their structures were confirmed by mass spectrometry and NMR spectroscopy. In contrast to ampicillin, the conjugates exhibited high antibacterial activity against Pseudomonas aeruginosa ATCC 15692 and ATCC 27853, effective only against the strain which is using the parent pyoverdin for iron uptake. This suggests that the conjugates enter the bacterial cell via the ferripyoverdin uptake pathway. Growth stimulation studies with conjugates hydrolysed

The Structure of the Pyoverdin from Pseudomonas fluorescens 1.3. Structural and Biological Relationships of Pyoverdins from Different Strains

“…The growth results reported above seem to show that identical or structurally very similar "key-sequences" can lead to a mutual acceptance, but that the requirements for the recognition are not of the same stringency for every strain, otherwise the same acceptance would be expected in both direc tions. The amino acids close to the chromophore apparently are not decisive for the recognition in agreement with the observation that a modifica tion of the basic amino acid (Lys in 4 or Arg in 3) does not hinder the transport into the cell (Kinzel et al, 1998;Kinzel and Budzikiewicz, 1999). A de cision, which of the possible explanations men tioned above for the acceptance of a foreign pyov erdin actually operates for a given strain, will only be possible when kinetic studies have been per formed and the identification of the receptor pro teins has been effected.…”

“…The variability of the peptide chain is closely con nected with the second function: It safeguards that a given ferri-pyoverdin is available only to the pro ducing strain because of a highly specific interac tion between the pyoverdin and a receptor outer membrane protein (Meyer et al, 1979). There are, however, examples known where Pseudomonas strains can accept pyoverdins differing in the pep tide chain from the one produced by themselves, as certain P. fluorescens and P. putida strains (Jacques et al, 1995) or P. aeruginosa ATCC 15692 that recognizes the pyoverdin of P. fluorescens ATCC 13525 (Hohnadel and Meyer, 1988;Kinzel et al, 1998). It is still an open question whether the foreign ferri-pyoverdin is accepted by the re ceptor of the own pyoverdin due to structural sim ilarities or whether a new receptor is developed (Koster et al, 1993).…”

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

“…Pyoverdine-ampicillin conjugates were shown to be more effective than ampicillin alone against P. aeruginosa, indicating enhanced entrance of the antibiotic (Kinzel et al, 1998). In a similar way, pyoverdine-fluoroquinolone conjugates showed promising bactericidal activity (Hennard et al, 2001).…”

Role of lung iron in determining the bacterial and host struggle in cystic fibrosis

“…There are several ways in which the iron homeostatic systems of P. aeruginosa may be exploited therapeutically. Conjugating antibiotics to siderophores to allow delivery direct to P. aeruginosa has been considered as part of a "Trojan horse" approach, but studies remain in their infancy (6,7,42,49,50). Interfering with P. aeruginosa iron uptake by blocking cell-surface receptors with cationic metals such as gallium or silver are promising approaches, which have been shown to inhibit P. aeruginosa biofilm formation and enhance antibiotic sensitivity (3,40,46,48,76).…”