The dissemination of multidrug-resistant bacteria has reduced the therapeutic efficacy of antibiotic drugs, and is now part of the major human healthcare emergencies. Among the bacteria ESKAPE, Gram negative pathogens such as Pseudomonas aeruginosa or Acinetobacter baumannii are very virulent. Bacteria require iron for many vital functions. However, in the oxidative atmosphere iron exists as insoluble salts what makes its bacterial assimilation hard. To overcome iron-deprivation, pathogens use small iron chelators named siderophores which transfert iron within bacteria by specific receptors. Siderophores are classed in four main families: hydroxamates, catecholates, carboxylates and phenolates. Previous studies have shown that the motif hydroxypyridinone is recognized by the same kind of transporters than catechol group. This chelating agent has recently been combined to a monosulfactam to lead to conjugate BAL30072 which is active on multidrugresistant strains of P. aeruginosa and A. baumannii. In previous researches, we have showed that aminoquinolinemethanols (AQMs), as mefloquine analogues, possess an antibacterial activity only against Gram positive bacteria. Inspired by the Trojan horse strategy, we have grafted hydroxypyridinone group to these AQMs with different linkers to obtain conjugates 1 and 2. Conjugate 1 is not active against P. aeruginosa DSM1117 while conjugate 2 possesses an interesting activity (MIC 128µg/mL). In order to better understand this difference of activity and to establish new structure activity relationships, we are now designing novel conjugates 3 with various linkers and iron chelators.

Design and synthesis of siderophore-antibiotic conjugates

254th National Meeting (2017)

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