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

Abstract

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.

Functional and Structural Analysis of the Siderophore Synthetase AsbB through Reconstitution of the Petrobactin Biosynthetic Pathway from Bacillus anthracis

“…Gaining deeper insights into the details of NIS-associated enzyme function might provide access to mechanism-based inhibitors, as have been demonstrated for nonribosomal peptide synthetase-derived siderophore adenylation domains (13,65,66). Moreover, development of the chemoenzymatic approach described in this work toward creating new siderophore analogs could be applied to generate a class of "Trojan horse" antibiotics, bearing improved target effects and IC 50 values compared with conventional chemotherapeutics (67,68). These practical considerations further highlight the importance of expanding our understanding of iron acquisition mechanisms employed by a vast array of pathogenic microbes.…”

One ring to rule them all: Current trends in combating bacterial resistance to the β‐lactams

“…As a result, bacteria have evolved aggressive and efficient iron acquisition systems involving the secretion of small iron chelating siderophores, whose main structural forms include the catecholates, hydroxamates, and citrate based polycarboxylates (reviewed in Refs. 89,90). In Gram-negative bacteria, these siderophores are taken up by high affinity outermembrane receptors that are often specific for individual siderophores (e.g., FepA, Cir, and Fiu catecholate receptors).…”

“…Secondly, the b-lactam conjugates can become active as a whole without having to be cleaved from the siderophore since the site of siderophore linkage is remote from the b-lactam active site. 89 …”

Involvement of Fe Uptake Systems and AmpC β-Lactamase in Susceptibility to the Siderophore Monosulfactam BAL30072 in Pseudomonas aeruginosa

“…Another option is to subvert the function of efficient and specialized transport systems to increase the uptake of antimicrobials. This "Trojan Horse" strategy (4,5) is exemplified by natural siderophore-antibiotic conjugates such as salmycins, albomycins (6), ferrimycins, and microcins (7) produced by various microorganisms. Inspired by these structures, synthetic siderophore conjugates have been designed in the past mainly as a combination between ␤-lactams and a catechol substituent to promote uptake through dedicated siderophore receptors (8)(9)(10)(11).…”