Metal-binding cyclodextrins: Synthesis and complexation with Zn²⁺ and Ga³⁺ cations towards antimicrobial applications

Highly resistant bacteria producing metallo-β-lactamases (MBLs) to evade β-lactam antibiotics, constitute a major cause of life-threatening infections world-wide. MBLs exert their hydrolytic action via Zn²⁺ cations in their active center. Presently, there are no approved drugs to target MBLs and combat the associated antimicrobial resistance (AMR). Towards this issue, we have prepared a family of cyclodextrins substituted with iminodiacetic acid (IDA) on their narrow side, while the wider side is either unmodified or per-2,3-O-methylated. The molecules form strong coordination complexes with Zn²⁺ or Ga³⁺ cations in aqueous solution. Free and metal-complexed compounds have been thoroughly characterized regarding structures, pH-dependent ionization states, distribution of species in solution, pKa values and metal-binding constants. At neutral pH the multi-anionic hosts bind up to four Zn²⁺ or Ga³⁺ cations. In vitro, 50 μΜ of the compounds achieve complete re-sensitization of MBL-producing Gram-negative clinical bacterial strains resistant to the carbapenems imipenem and meropenem. Moreover, the radioactive complex [⁶⁷Ga]Ga-β-IDACYD prepared, displays high radiochemical purity, sufficient stability both overtime and in the presence of human plasma apo-transferrin, thus providing an invaluable tool for future biodistribution and pharmacokinetic studies of β-IDACYDin vivo, prerequisites for the development of therapeutic protocols.