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Abstract
Gram-negative bacteria’s resistance such as Pseudomonas aeruginosa and the Burkholderia group to conventional antibiotics leads to therapeutic failure. Use of siderophores as Trojan horses to internalize antibacterial agents or toxic metals within bacteria is a promising strategy to overcome resistance phenomenon. To combat the Pseudomonas sp, we have synthesized and studied two piperazine-based siderophore mimetics carrying either catecholate moieties (1) or hydroxypyridinone groups (2) as iron chelators. These siderophore-like molecules were prepared in no more than four steps with good global yields. The physicochemical study has highlighted a strong iron affinity since their pFe values were higher than 20. 1 possesses even a pFe value superior than those of pyoverdine, the P. aeruginosa endogenous siderophore, suggesting its potential ability to compete with it. At physiological pH, 1 forms mainly a 2:3 complex with iron, whereas two species are observed for 2. Unfortunately, the corresponding Ga(III)-1 and 2 complexes showed no antibacterial activity against P. aeruginosa DSM 1117 strain. The evaluation of their siderophore-like activity showed that 1 and 2 could be internalized by the bacteria.
Highlights
Among Gram-negative bacteria, Pseudomonas aeruginosa and Burkholderia pseudomallei are worrying
The corresponding Ga(III)-1 and 2 complexes showed no antibacterial activity against P. aeruginosa DSM 1117 strain
The antibacterial activity of the siderophore mimetics 1 and 2 was measured on P. aeruginosa DSM 1117 in both cation-supplemented Mueller-Hinton (MH) Broth, as advised by the Clinical and Laboratory Standards Institute (CLSI) [38], and in Succinate Minimum Medium (SMM), a medium virtually deprived of iron
Summary
Among Gram-negative bacteria, Pseudomonas aeruginosa and Burkholderia pseudomallei are worrying. P. aeruginosa secures its iron acquisition by internalization of Pvd and Pch, recognized respectively by the FpvA (or FpvB) and FptA [14] This strain is able to use exogenous iron chelators through the expression of different OMRs such as FecA (for ferric citrate), PfeA and PirA (for enterobactin), FoxA and FiuA (for DFO and ferrichrome), FemA (for mycobactin) and ChtA (for rhizobactin and aerobactin) [6]. Many recent studies reported the antimicrobial potential of N-substituted piperazines [26] Particular compounds such as 1-(1-naphtylmethyl)-piperazine are known to act as efflux pump inhibitors helping to restore antibiotic activity on resistant strains [28].
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