Staphyloferrin A as siderophore-component in fluoroquinolone-based Trojan horse antibiotics

Abstract

A series of fluoroquinolone conjugates was synthesised by linking the carboxylic acid functionality of the carboxylate-type siderophore staphyloferrin A and its derivatives to the piperazinyl nitrogen of ciprofloxacin and norfloxacin via amide bond formation. Four siderophore-drug conjugates were screened against a panel of bacteria associated with infection in humans. Whilst no activity was found against ciprofloxacin- or norfloxacin-resistant bacteria, one of the conjugates retained antibacterial activity against fluoroquinolone-susceptible strains although the structure of its lysine-based siderophore component differs from that of the natural siderophore staphyloferrin A. In contrast, three ornithine-based siderophore conjugates showed significantly reduced activity against strains that are susceptible to their respective parent fluoroquinolones, regardless of the type of fluoroquinolone attached or chirality at the ornithine Cα-atom. The loss of potency observed for the (R)- and (S)-ornithine-based ciprofloxacin conjugates correlates with their reduced inhibitory activity against the target enzyme DNA gyrase.

Microbial siderophores and their potential applications: a review

“…The hydrophilicity nature of staphyloferrin A improves the water solubility of its conjugates and enhances the rate of transport of the drug to the cell (Milner et al 2013). Since Staphylococcus aureus secretes staphyloferrin siderophores, Milner et al synthesized a series of novel staphyloferrin based Trojan horse conjugates and tested the antimicrobial properties of those conjugates on Staphylococcus aureus (Milner et al 2013). It was reported that one of the conjugate was found to exhibit antimicrobial property against Staphylococcus aureus (Milner et al 2013).…”

“…Since Staphylococcus aureus secretes staphyloferrin siderophores, Milner et al synthesized a series of novel staphyloferrin based Trojan horse conjugates and tested the antimicrobial properties of those conjugates on Staphylococcus aureus (Milner et al 2013). It was reported that one of the conjugate was found to exhibit antimicrobial property against Staphylococcus aureus (Milner et al 2013). Staphylococcus aureus can colonize human skin and gut and associates with some problematic health-care-associated infections, including surgical site infections, bacteraemias, and lower respiratory tract infections (Milner et al 2013).…”

“…Once inside the cell, siderophore-beta-lactam antibiotic complex binds to penicillin-binding proteins present in the periplasm and inhibit the growth of gram-negative bacteria (Brochu et al 1992). To date, mainly catecholate and hydroxamate types of siderophores are used as delivery vehicles for antimicrobials to overcome membrane-permeation-based drug access problems (Milner et al 2013). However, carboxylate-type siderophores, such as staphyloferrin A, can be a good option for certain applications, as this type of siderophore showed better iron chelating property in acidic environments than catecholate and hydroxamate siderophores (Milner et al 2013).…”

“…To date, mainly catecholate and hydroxamate types of siderophores are used as delivery vehicles for antimicrobials to overcome membrane-permeation-based drug access problems (Milner et al 2013). However, carboxylate-type siderophores, such as staphyloferrin A, can be a good option for certain applications, as this type of siderophore showed better iron chelating property in acidic environments than catecholate and hydroxamate siderophores (Milner et al 2013). The hydrophilicity nature of staphyloferrin A improves the water solubility of its conjugates and enhances the rate of transport of the drug to the cell (Milner et al 2013).…”

“…However, carboxylate-type siderophores, such as staphyloferrin A, can be a good option for certain applications, as this type of siderophore showed better iron chelating property in acidic environments than catecholate and hydroxamate siderophores (Milner et al 2013). The hydrophilicity nature of staphyloferrin A improves the water solubility of its conjugates and enhances the rate of transport of the drug to the cell (Milner et al 2013). Since Staphylococcus aureus secretes staphyloferrin siderophores, Milner et al synthesized a series of novel staphyloferrin based Trojan horse conjugates and tested the antimicrobial properties of those conjugates on Staphylococcus aureus (Milner et al 2013).…”