Among Gram-negative bacteria, Pseudomonas aeruginosa and Burkholderia pseudomallei are particularly worrying. P. aeruginosa is often involved in nosocomial infections (6,2% of infected hospitalized patients) and B. pseudomallei, formerly classified as P. pseudomallei, causes melioidosis which prevails in tropical climates. The most common form of the Whitmore disease, pulmonary melioidosis, resembling tuberculosis, is particularly recalcitrant to therapy and has a high relapse rate. We are interested in the development of new ways to combat the Pseudomonas group, targeted due to its high level of resistance to antibiotics via a lack of membrane permeability or efflux. Using iron transport systems is a promising strategy to overcome this phenomenon by restoring the activity of conventional antibiotics. Indeed, iron is a micronutrient necessary for the survival of bacteria. It is essential to many biological processes such as respiration, DNA synthesis… However, the ferric iron has a low bioavailability due to its low solubility in water. Under iron limited conditions, many bacteria synthesize molecules of low molecular weight, called siderophores, able to chelate the surrounding iron. According to their kind, bacteria express different types of outer membrane receptors (OMR) that recognize their endogenous siderophores but also xenosiderophores or synthetic siderophores. In particular, P. aeruginosa and B. pseudomallei possess catecholate receptors. Thus, we exploited a piperazine platform to graft iron chelator group, such as catecholate and its bioisostere, hydroxypyridinone group, to form siderophore analogs which can be recognized by the Pseudomonas sp. After synthesis, physicochemical properties of the siderophore (pFe and coordination mode of the metal) as well as the effective transport of the corresponding Sid-Fe(III) complexes through iron uptake pathways will be evaluated. Finally, the siderophores with the best Pseudomonas OMR recognition and iron chelation capacities will be chosen to form siderophore-antibiotic conjugates or toxic siderophore-gallium complexes.

New piperazine-based siderophore-antibiotic conjugates to fight antimicrobial resistance

2019 Fall National Meeting

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