Synthesis and antimicrobial activity of an SO2-releasing siderophore conjugate

A novel Trojan Horse conjugate consisting of an SO2-releasing 2,4-dinitrobenzenesulfonamide group attached to the monocatecholate siderophore aminochelin was synthesized to examine whether a bidentate catecholate siderophore unit could help potentiate the antimicrobial activity of SO2-releasing prodrugs. The conjugate obtained displays rapid SO2 release on reaction with glutathione, and proved more active against Staphylococcus aureus than a comparable SO2-releasing prodrug lacking the siderophore unit, although activity required micromolar concentrations. The conjugate was inactive against wild-type Escherichia coli, but activity was observed against an entA mutant strain that is unable to produce its major siderophores. Hence, the poor activity of the conjugate in wild-type E. coli may be due to the production of native siderophores that can compete with the conjugate for iron binding and uptake. Trojan Horse approach: the attachment of an iron-binding didentate catecholate siderophore unit potentiates the antimicrobial activity of an SO2-releasing prodrug in S. aureus. [Display omitted] •Synthesis of siderophore-based 2,4-dinitrobenzenesulfonamide conjugate and 3 analogues.•Rapid SO2 release from the siderophore conjugate upon reaction with glutathione.•Siderophore-enhanced antibacterial activity against Staphylococcus aureus.•The conjugate was inactive against wild-type Escherichia coli.•Activity was observed against E. coli mutant unable to produce own siderophores.