Iron transport-mediated drug delivery using mixed-ligand siderophore-β-lactam conjugates

Ghosh, Arun K.; Ghosh, Monisha; Niu, Chuan; Malouin, François; Moellmann, Ute; Miller, Marvin J.

doi:10.1016/s1074-5521(96)90167-2

Cited by 81 publications

(94 citation statements)

References 19 publications

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“…The use of mixed ligand-siderophore that can be taken up via several pathways is seen as advantage since it reduces the frequency of resistant mutants and, if occurring, makes them more susceptible to iron starvation since the transport systems were found to be the main targets for resistance formation rather than the antibiotic targets themselves. The advantage of mixedligand siderophore conjugates was proven with various antibiotic functions, and activity of a biscatechol-hydroxamate-carbacephem conjugate that was more than 2,000-fold higher than that of to the parent drug loracarbef (Lorabid) could be reached in Acinetobacter (MIC ϭ 0.03 g/ml) (110,113). The antibiotic functions of the conjugates tested so far are quite diverse.…”

Section: "Trojan Horse" Antibioticsmentioning

confidence: 99%

Siderophore-Based Iron Acquisition and Pathogen Control

Miethke

Marahiel

2007

Microbiol Mol Biol Rev

1,413

1,302

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SUMMARY High-affinity iron acquisition is mediated by siderophore-dependent pathways in the majority of pathogenic and nonpathogenic bacteria and fungi. Considerable progress has been made in characterizing and understanding mechanisms of siderophore synthesis, secretion, iron scavenging, and siderophore-delivered iron uptake and its release. The regulation of siderophore pathways reveals multilayer networks at the transcriptional and posttranscriptional levels. Due to the key role of many siderophores during virulence, coevolution led to sophisticated strategies of siderophore neutralization by mammals and (re)utilization by bacterial pathogens. Surprisingly, hosts also developed essential siderophore-based iron delivery and cell conversion pathways, which are of interest for diagnostic and therapeutic studies. In the last decades, natural and synthetic compounds have gained attention as potential therapeutics for iron-dependent treatment of infections and further diseases. Promising results for pathogen inhibition were obtained with various siderophore-antibiotic conjugates acting as “Trojan horse” toxins and siderophore pathway inhibitors. In this article, general aspects of siderophore-mediated iron acquisition, recent findings regarding iron-related pathogen-host interactions, and current strategies for iron-dependent pathogen control will be reviewed. Further concepts including the inhibition of novel siderophore pathway targets are discussed.

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Section: "Trojan Horse" Antibioticsmentioning

confidence: 99%

Siderophore-Based Iron Acquisition and Pathogen Control

Miethke

Marahiel

2007

Microbiol Mol Biol Rev

1,413

1,302

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“…These were mainly cephalosporins, carbacephalosporins, carbapenems or monobactams with one or two catecholate or mixed catecholate hydroxamate moieties. (Arisawa et al 1991;Ghosh et al 1996;Chang et al 1997;Roosenberg et al 2000). Antibacterial activity of the SDCs was increased when compared to those of the nonmodified drugs under conditions of iron starvation, preferentially against P. aeruginosa strains.…”

Section: Introductionmentioning

confidence: 99%

Siderophores as drug delivery agents: application of the “Trojan Horse” strategy

et al. 2009

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The outer membrane permeability barrier is an important resistance factor of bacterial pathogens. In combination with drug inactivating enzymes, target alteration and efflux, it can increase resistance dramatically. A strategy to overcome this membrane-mediated resistance is the misuse of bacterial transport systems. Most promising are those for iron transport. They are vital for virulence and survival of bacteria in the infected host, where iron depletion is a defense mechanism against invading pathogens. We synthesized biomimetic siderophores as shuttle vectors for active transport of antibiotics through the bacterial membrane. Structure activity relationship studies resulted in siderophore aminopenicillin conjugates that were highly active against Gram-negative pathogens which play a crucial role in destructive lung infections in cystic fibrosis patients and in severe nosocomial infections. The mechanism of action and the uptake of the compounds via specific iron siderophore transport routes were demonstrated. The novel conjugates were active against systemic Pseudomonas aeruginosa infections in mice with ED(50) values comparable to the quinolone ofloxacin and show low toxicity.

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“…Theoretically, this provides a gateway for targeted delivery of antibacterial agents to pathogens without affecting the human or animal host. An effective antibiotic conjugated with a siderophore specific for a pathogen would be taken up through the iron uptake systems of the pathogen, thus providing a Trojan horse approach against bacterial infection in vivo (Braun, 1999;Ghosh et al, 1996).…”

Section: Introductionmentioning

confidence: 99%