Trojan horse strategy: synthesis of piperazine-based siderophores

Resistance to antibiotics is an emerging phenomenon and a major medical problem. The resistance of Gram-negative bacteria such as Pseudomonas aeruginosa and the Burkholderia group to conventional antibiotics leads to therapeutic failure and requires new antibiotic therapies. The use of iron transport systems is a promising strategy to overcome this phenomenon. These TonB-dependent receptors, essential for the survival of microorganisms, allow specific recognition of ferric siderophore complexes in order to transport iron within bacteria1. Bacteria, according to their kind, express different types of receptors that allow them to recognize their endogenous siderophores but also xenosiderophores. Pseudomonas aeruginosa and Burkholderia pseudomallei in particular possess FptA receptors allowing the recognition of pyochelin.2 These specific systems may allow the introduction of antibacterial agents by forming antibiotic-siderophore conjugates or toxic complexes such as gallium complexes, in the bacteria to kill it. Siderophores have three types of chelating function: catechols, hydroxamates and hydroxy-carboxylates. Previous work in the laboratory has shown that piperazine 1,4-dicatechol structures (MPPS0225) could be recognized by Pseudomonas aeruginosa strains. In order to further investigate this piperazine platform, we have synthesized iron chelators bearing 3-hydroxypyridin-4-ones and 1,3-dihydroxypyridin-4-one ligands. At the same time, we were interested in the synthesis of a more complex 2,5-dioxopiperazine platform, part of the rhodotorulic acid (RA), a natural siderophore produced by Rhodotorula pilimanae showing an interesting iron affinity (pFe = 21,8). Two RA synthesis strategies will be developed as well as the corresponding 3,6-disubstituted analogs. Through the synthesis of these chelators, we would like to study the influence, on the iron complexation, of: i) the nitrogen platform (piperazine or dioxopiperazine), ii) the presence of stereogenic centers (3,6-disubstituted dioxopiperazine vs 1,4 -disubstituted piperazines) and iii) the nature of the iron ligands (hydroxypyridinone vs catechol). An evaluation of the siderophore-like potential and a measurement of the complexing force will be carried out. We would like to thank the DGA and the Haut de France region for their financial support. References Miethke M.; Marahiel MA. Microbiology and Molecular Biology Reviews. 2007, 71, 413-451. Butt AT.; Thomas MS. Frontiers in Cellular and Infection Microbiology. 2017, 7.