Selenazolinium Salts as "Small Molecule Catalysts" with High Potency against ESKAPE Bacterial Pathogens.
Karolina WitekMuhammad Jawad NasimMarkus BischoffRosmarie GauppPavel ArsenyanJelena VasiljevaMałgorzata Anna MarćAgnieszka OlejarzGniewomir LataczKatarzyna Kieć-KononowiczJadwiga HandzlikClaus JacobPublished in: Molecules (Basel, Switzerland) (2017)
In view of the pressing need to identify new antibacterial agents able to combat multidrug-resistant bacteria, we investigated a series of fused selenazolinium derivatives (1-8) regarding their in vitro antimicrobial activities against 25 ESKAPE-pathogen strains. Ebselen was used as reference compound. Most of the selenocompounds demonstrated an excellent in vitro activity against all S. aureus strains, with activities comparable to or even exceeding the one of ebselen. In contrast to ebselen, some selenazolinium derivatives (1, 3, and 7) even displayed significant actions against all Gram-negative pathogens tested. The 3-bromo-2-(1-hydroxy-1-methylethyl)[1,2]selenazolo[2,3-a]pyridinium chloride (1) was particularly active (minimum inhibitory concentrations, MICs: 0.31-1.24 µg/mL for MRSA, and 0.31-2.48 µg/mL for Gram-negative bacteria) and devoid of any significant mutagenicity in the Ames assay. Our preliminary mechanistic studies in cell culture indicated that their mode of action is likely to be associated with an alteration of intracellular levels of glutathione and cysteine thiols of different proteins in the bacterial cells, hence supporting the idea that such compounds interact with the intracellular thiolstat. This alteration of pivotal cysteine residues is most likely the result of a direct or catalytic oxidative modification of such residues by the highly reactive selenium species (RSeS) employed.
Keyphrases
- gram negative
- multidrug resistant
- small molecule
- staphylococcus aureus
- drug resistant
- escherichia coli
- acinetobacter baumannii
- induced apoptosis
- klebsiella pneumoniae
- fluorescent probe
- reactive oxygen species
- cell cycle arrest
- living cells
- methicillin resistant staphylococcus aureus
- magnetic resonance
- high throughput
- structure activity relationship
- protein protein
- candida albicans
- ionic liquid
- endoplasmic reticulum stress
- highly efficient
- signaling pathway
- magnetic resonance imaging
- silver nanoparticles
- cell death
- oxidative stress
- cystic fibrosis
- contrast enhanced
- mass spectrometry
- transition metal
- single cell