Multivalent Siderophore–DOTAM Conjugates as Theranostics for Imaging and Treatment of Bacterial Infections

Abstract

There is a strong need to better diagnose infections at deep body sites through noninvasive molecular imaging methods. Herein, we describe the synthesis and characterization of probes based on siderophore conjugates with catechol moieties and a central DOTAM scaffold. The probes can accommodate a metal ion as well as an antibiotic moiety and are therefore suited for theranostic purposes. The translocation of the conjugates across the outer and inner cell membranes of E. coli was confirmed by growth recovery experiments with enterobactin-deficient strains, by the antibacterial activity of ampicillin conjugates, and by confocal imaging using a fluorogen-activating protein-malachite green system adapted to E. coli. The suitability of the probes for in vivo imaging was demonstrated with a Cy5.5 conjugate in mice infected with P. aeruginosa.

The Scope of Application of Macrocyclic Polyamines Beyond Metal Chelation

“…This approach was further exploited by Brönstrup and co‐workers through the use of multivalent siderophore‐DOTA conjugates for targeting bacteria . The introduction of three O ‐acetyl‐2,3‐dihydroxybenzoic acid units on the DOTA scaffold via amide linkages made the resulting conjugate capable of capturing and firmly chelating iron (i.e., acting as a siderophore after hydrolysis of its acetate moieties by bacterial esterases and may be regarded as an enterobactin analog) .…”

Eisenaufnahme in Pilzen der Gattung Aspergillus: strukturelle und biochemische Einblicke in Siderophoresterasen

“…[4,7] Die genauen Wechselwirkungen zwischen hydrolytischen und reduktiven Prozessen während der Eisenfreisetzung bleiben jedoch -s elbst in den besser charakterisierten bakteriellen Systemen -w eitestgehend unklar. [28] Danksagung Diese Arbeit wurde durch das D-A-CH-Programm (Deutsche Forschungsgemeinsschaft GR 1861/8-1 an M.G.u nd Wissenschaftsfonds FWF I1346-B21 an H.H.) [27] Aktuelle Studien beschäftigen sich bereits mit der Anwendung von Siderophor-Konjugaten bei der Bildgebung und Bekämpfung bakterieller Krankheiten, wovon eine die intrazelluläre Siderophor-Hydrolyse durch Esterasen als fürd ie zytotoxische Aktivitätz wingend notwendig beschreibt.…”

“…[27] Aktuelle Studien beschäftigen sich bereits mit der Anwendung von Siderophor-Konjugaten bei der Bildgebung und Bekämpfung bakterieller Krankheiten, wovon eine die intrazelluläre Siderophor-Hydrolyse durch Esterasen als fürd ie zytotoxische Aktivitätz wingend notwendig beschreibt. [28] Stichwçrter: Eisenmetabolismus ·Hydrolyse ·P ilze · Siderophore ·T etraedrisches Intermediat…”

Iron Scavenging in Aspergillus Species: Structural and Biochemical Insights into Fungal Siderophore Esterases

“…[4,7] Thep recise interplay between hydrolytic and reductive processes during iron release however still remains uncertain, even in bettercharacterized bacterial systems. [28] Figure 5. [27] Regarding bacteria, recent studies have shown the use of diverse siderophore conjugates to image and combat infections,with one describing intracellular hydrolysis by esterases as being vital for the desired cytotoxic activity.…”

“…[27] Regarding bacteria, recent studies have shown the use of diverse siderophore conjugates to image and combat infections,with one describing intracellular hydrolysis by esterases as being vital for the desired cytotoxic activity. [28] Figure 5. The architectureofthe active site differs significantly between the analyzed esterases.…”