Investigating the antibacterial activity of salen/salophene metal complexes: Induction of ferroptosis as part of the mode of action

Abstract

The continuous increase of resistant bacteria including Staphylococcus aureus and its methicillin-resistant phenotype (MRSA) is currently one of the major challenges in medicine. Therefore, the discovery of novel lead structures for the design of drugs to fight against infections caused by these bacteria is urgently needed. In this structure-activity relationship study, metal-based drugs were investigated for the treatment of resistant pathogens. The selected Ni(II), Cu(II), Zn(II), Mn(III), and Fe(II/III) complexes differ in their salen- and salophene-type Schiff base ligands. The in vitro activity was evaluated using gram-positive (S. aureus and MRSA) and gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Especially the iron(III) complexes displayed promising antimicrobial effects against gram-positive bacteria, with MIC₉₀ values ranging from 0.781 to 50 μg/mL. Among them, chlorido[(N,N'-bis(salicylidene)-1,2-phenylenediamine]iron(III) (6) showed the best MIC₉₀ value (0.781 μg/mL = 1.93 μmol/L) against S. aureus and MRSA. Complex 6 was comparably potent as ciprofloxacin against S. aureus (0.391 μg/mL = 1.18 μmol/L) and only marginally less active than tetracycline against MRSA (0.391 μg/mL = 0.88 μmol/L). As part of the mode of action, ferroptosis was identified. Applying compound 6 (10 μg/mL), both gram-positive strains grown in PBS were killed within 20 min. This efficacy basically documents that salophene iron(III) complexes represent possible lead structures for the further development of antibacterial metal complexes.

Keywords: Antibacterial activity; Ferroptosis; MRSA; Metal complexes; Staphylococcus aureus; Time-kill kinetics.