Design, Synthesis and Characterization of Artificial Siderophores and their Conjugates

Abstract

An emergence of infections with multidrug-resistant Gram negative bacteria accompanied by a decline in new classes of antibiotics over the past few decades poses a serious concern to global health today. A major technical challenge to the advancement of effective antibiotics targeting Gram-negative bacteria is the low permeability of their outer membrane against small molecules, which represent most drugs currently available. This work employs the Trojan Horse strategy to overcome the challenge, by using drug-loaded siderophores to exploit the active iron transport systems in these pathogens. While artificial siderophores, for example based on DOTAM and MECAM cores, to deliver imaging moieties or antibiotics have been reported, knowledge on the influence of core geometry and size on siderophore activity remains limited. This work describes the design, synthesis and preliminary characterization of artificial tris(catecholate) siderophores with a cyclopropane core of defined stereochemistry. The cyclopropane core includes three cis-oriented arms for iron chelation, and one trans-oriented arm for the attachment of imaging moieties or antibiotics. The conjugation of one such siderophore to ampicillin, a broad spectrum antibiotic, was also achieved. The iron-binding ability of the synthesized siderophores was assessed in a competitive binding experiment using Chrome Azurol S. Upon further microbiological evaluation, these siderophores and the siderophore-antibiotic conjugate may potentially be developed to candidates for in vivo pharmacological studies.