Metal-binding cyclodextrins: Synthesis and complexation with Zn2+ and Ga3+ cations towards antimicrobial applications.
Carbohydr Polym
; 321: 121323, 2023 Dec 01.
Article
in En
| MEDLINE
| ID: mdl-37739545
ABSTRACT
Highly resistant bacteria producing metallo-ß-lactamases (MBLs) to evade ß-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-ß-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 ß-IDACYDin vivo, prerequisites for the development of therapeutic protocols.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cyclodextrins
/
Coordination Complexes
/
Anti-Infective Agents
Type of study:
Guideline
Limits:
Humans
Language:
En
Journal:
Carbohydr Polym
Year:
2023
Document type:
Article