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Metal Ion Dependent Antibiotics in Chemotherapy
Published in Astrid Sigel, Helmut Sigel, Metal Ions in Biological Systems, 2004
David H. Petering, Chuanwu Xia, William E. Antholine
Albomycin, like bacterial siderophores, binds to an outer membrane receptor/transporter (fhuA in E. coli) and is moved into the periplasmic space in an energy dependent process that involves a second protein, TonB [137,138]. There it associates with another protein, fluD [139]. Finally, it moves into the cell through the inner membrane in an ATP-dependent process. Once in the cell, peptidase N hydrolyzes the structure, releasing the active antibiotic moiety [134,139].
Iron metabolism in Pseudomonas aeruginosa biofilm and the involved iron-targeted anti-biofilm strategies
Published in Journal of Drug Targeting, 2021
Yapeng Zhang, Xuanhe Pan, Linqian Wang, Liyu Chen
The cause that pathogens develop antibiotic resistance lies in the decreased permeability of the bacterial extracellular membrane and the biofilm. For example, the negatively charged biofilm matrix polymers could prevent positively charged antibiotics (like aminoglycosides or polypeptides) from passing through the biofilm by binding to the matrix [71]. However, most of the antibiotics used to defend P. aeruginosa infections have to penetrate the cell membrane to reach the intracellular target, thus restraining the bacteria growth or killing the cells as the bactericides do. Many natural or artificial siderophores are produced as delivery vehicles for antimicrobials to overcome membrane-penetrating difficulty, which called ‘Trojan horse’ strategy [72]. In this delivery system, the artificially synthesised siderophore-antibiotic conjugate can enter the cell when recognised by certain receptors and then release the antibiotics for sterilisation. Sideromycin, including danomycin, salmycin, albomycin, ferrimycin and microcin, are a range of toxic substances produced by other microorganisms [72]. In recent years, sideromycin has been found to be a promising drug for the treatment of bacterial infection by taking the ‘Trojan horse’ strategy. Besides, the siderophore-β-lactam antibiotic conjugate is known to have antibacterial effects on curbing the gram-negative bacteria to multiply [73]; the synthetic siderophores of desferrioxamine and desferrioxamine-caffeine, acted as gallium-carriers via the ‘Trojan Horse’ scheme, could boost up the anti-biofilm activity of gallium [74].
Novel pyochelin-based PEGylated liposomes for enhanced delivery of antibiotics against resistant clinical isolates of Pseudomonas aeruginosa
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Pradeep Pushparaj Selvadoss, Jayshree Nellore, Malathy Balaraman Ravindrran, Uma Sekar
During iron-limiting conditions, bacteria excrete iron chelators, siderophores, for high-affinity iron uptake and transport it back into the cell [13–16]. The use of siderophore–antibiotic conjugate for the treatment of many bacterial infections is a powerful approach in targeted drug delivery system [17–19]. Pyochelin (Pch) is a major siderophore of P. aeruginosa which is sensed by FptA receptor on its outer membrane [20–22]. One well-studied antibiotic through this concept is albomycin, a siderophore synthesized by Streptomyces, in which the ferric hydroxamate carrier is attached to antibiotic thioribosyl pyrimidine and taken up by the outer membrane [23].
Discovery of natural products with metal-binding properties as promising antibacterial agents
Published in Expert Opinion on Drug Discovery, 2019
Prasad Dandawate, Subhash Padhye, Rainer Schobert, Bernhard Biersack
Aside from their direct antibiotic activity, catechol derivatives can also be applied for drug targeting. Bacteria use species-specific small molecule siderophores to sequester and internalise essential iron, and many siderophores display catechol moieties as chelated ligands to bind Fe(III) ions [4]. Siderophores can be subdivided in pure catecholates (e.g., enterobactin, bazillibactin, vibriobactin), mixed derivatives with catecholates and hydroxamates (azotobactin, poverdine), and pure hydroxamates (ferrichrome) [4]. Conjugation of an antibiotic drug to a siderophore fragment can increase the active uptake of the drug component by bacterial ferrisiderophore transporter systems when compared with the original antibiotic without siderophore. In addition, such a siderophore-conjugation can enhance the specificity of the drug molecule when strain specific siderophores are applied. Naturally occurring examples such as ´´Trojan Horse´´ siderophores loaded with antibiotic warheads include sideromycins (salmycin, albomycin δ2) and microcins 11 (Figure 2) [4]. Genome mining led to the discovery of more natural siderophore antibiotics such as the microcins MccM and MccH47 from microcidin-generating Klebsiella and Escherichia strains, however, they were less active than the known MccE492 [4]. Synthetic Trojan Horses were also frequently prepared over the last years. Mixed biscatechol-hydroxamate conjugates 12 with a penicillin-based ester prodrug derivative were prepared via multiple application of the ketene-ylide Ph3PCCO in reactions with aldehydes and alcohols or amines. Compounds 12 displayed functional siderophoric properties as to tests with siderophore-deficient E. coli strains (Figure 2) [4]. Cefiderocol (13), another siderophore-penicillin conjugate developed by Shionogi, has entered clinical phase 2/3 trials (Figure 2) [4]. Catecholate siderophores were also successfully attached to fluoroquinolone antibiotics like in the pyoverdin derivative 14 (Figure 2) [4].