Is drug release necessary for antimicrobial activity of siderophore-drug conjugates? Syntheses and biological studies of the naturally occurring salmycin “Trojan Horse” antibiotics and synthetic desferridanoxamine-antibiotic conjugates

Abstract

The recent rise in drug resistance found amongst community acquired infections has sparked renewed interest in developing antimicrobial agents that target resistant organisms and limit the natural selection of immune variants. Recent discoveries have shown that iron uptake systems in bacteria and fungi are suitable targets for developing such therapeutic agents. The use of siderophore-drug conjugates as "Trojan Horse" drug delivery agents has attracted particular interest in this area. This review will discuss efforts in our research group to study the salmycin class of "Trojan Horse" antibiotics. Inspired by the natural design of the salmycins, a series of desferridanoxamine-antibiotic conjugates were synthesized and tested in microbial growth inhibition assays. The results of these studies will be related to understanding the role of drug release in siderophore-mediated drug delivery with implications for future siderophore-drug conjugate design.

The Pseudomonas aeruginosa PA14 ABC Transporter NppA1A2BCD Is Required for Uptake of Peptidyl Nucleoside Antibiotics

“…P. aeruginosa possesses two TonB-dependent transporters, FiuA and FoxA, that are responsible for the uptake of hydroxamate siderophores, including ferrichrome, across the outer membrane (42,43). Albomycin displays only weak bactericidal activity against P. aeruginosa (44,45). This allows speculation that cleavage of albomycin inside the cell and/or detoxification of its toxic payload is the limiting factor that modulates its bactericidal activity in P. aeruginosa.…”

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

“…This concept is based on the naturally occurring sideromycin antibiotics that mimic siderophores to gain intracellular access (Braun et al, 2009). Over the past three decades, numerous conjugates linking a siderophore or a siderophore mimic to different antibiotics via a linker molecule have been synthesized with varying degrees of antimicrobial efficacy (Möllmann et al, 2009;Wencewicz et al, 2009;Zeng et al, 2012;Fardeau et al, 2014). This approach, known as the 'Trojan horse' strategy, has been the subject of several reviews (including those by de Carvalho & Fernandes, 2014;Gó rska et al, 2014;Mislin & Schalk, 2014).…”

Structural basis, chemical driving forces and biological implications of flavones as Cu(II) ionophores

“…Thus, releasing and subsequent accumulation of Cu(I) induce collapse of the redox buffering system (Figure 3G-I). From this perspective, 3-HF-Cu inside the cells can be viewed as a "Trojan horse"[56] which is capable of disrupting the redox regulation programs.To further show evidence that Cu(II) dissociates from the complex 3-HF-Cu in the reductive cytoplasm, we used a NIR fluorescent Cu(I) probe based on the tricarbocyanine fluorophore and the Cu(I) receptor BETA[29] to image intracellular Cu(I) accumulation. As shown inFigure 8, the increased red fluorescence (indicative of intracellular Cu(I) accumulation) was observed when HepG2 cells were treated with 3-HF and Cu(II), compared to 3-HF and Cu(II) only.…”