Synthesis of novel siderophores for the investigation of the pore size of transmembrane siderophore-receptors and development of siderophore conjugates for the diagnosis of infections with Gram-negative bacteria

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In the view of growing resistance of pathogenic, Gram-negative bacteria against established antibiotics, the development of novel antimicrobials and concepts to fight and detect pathogenic bacteria is of enormous importance. An innovative strategy for the development of novel antibiotics against Gram-negative bacteria is based on the conjugation of antimicrobial drugs to siderophores, small molecule iron-binders, known to be actively transported across the cell wall barrier of Gram-negative bacteria through recognition by specific siderophore receptors. Such Trojan Horse conjugates can actively deliver drugs or reporter molecules to bacteria and accumulate them inside. Especially, Enterobactin and Salmochelins, which are high affinity iron binders, playing an important role for iron accumulation during infection in human hosts, are in the focus of the development of novel siderophore conjugates. However, to date there is only limited information on the actual size of the transient pore of the transmembrane siderophore receptors opened after siderophore recognition. The present project aims of developing Enterobactin and Salmochelin derivatives bearing a novel attachment point for effector molecules in the backbone of the siderophores outside of the area important for recognition. Based on these siderophores novel stimuli-responsive siderophore-reporter conjugates for the detection of bacteria are planned to be synthesized. Therefore, novel latent fluorescent Rhodamin-based reporter molecules bearing an azo-reductase-responsive amino-trimethyl-lock-trigger should be developed, which are supposed to be activated upon siderophore-mediated uptake into bacteria by intracellular azo-reductases. Additionally, NIR-fluorescent indoheptacyanin-based reporter molecules with a para-nitrobenzyl-trigger are planned to be created, which are supposed to show a fluorescence shift to the red, visible wavelength upon reduction by intracellular nitro-reductases. Furthermore, based on the presented siderophores the development of conjugates with size-defined dummy payloads as well as stimuli-sensitive [2]-rotaxane-siderophore-reporter conjugates are envisaged, which for the first time should allow the investigation of the pores of siderophore receptors FepA and IroN concerning size, rigidity and polarity of potential conjugate payloads. The resulting data on structure-activity-relationships are planned to enable the design and development of antimicrobial siderophore-drug conjugates based on the presented siderophores for the treatment of infections with Gram-negative bacteria within a follow up grant application.