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Molecules 2017, 22(12), 2174; https://doi.org/10.3390/molecules22122174

Selenazolinium Salts as “Small Molecule Catalysts” with High Potency against ESKAPE Bacterial Pathogens

1
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Cracow, Poland
2
Bioorganic Chemistry, School of Pharmacy, University of Saarland, Campus B2.1, D-66123 Saarbruecken, Germany
3
Institute of Medical Microbiology and Hygiene, Saarland University, D-66421 Homburg, Germany
4
Department of Medicinal Chemistry, Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 3 November 2017 / Revised: 29 November 2017 / Accepted: 5 December 2017 / Published: 8 December 2017
(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)
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Abstract

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 (18) 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. View Full-Text
Keywords: selenazolinium salts; ebselen; RSeS; multidrug resistance; MRSA; ESKAPE pathogens; antibacterial agents selenazolinium salts; ebselen; RSeS; multidrug resistance; MRSA; ESKAPE pathogens; antibacterial agents
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Witek, K.; Nasim, M.J.; Bischoff, M.; Gaupp, R.; Arsenyan, P.; Vasiljeva, J.; Marć, M.A.; Olejarz, A.; Latacz, G.; Kieć-Kononowicz, K.; Handzlik, J.; Jacob, C. Selenazolinium Salts as “Small Molecule Catalysts” with High Potency against ESKAPE Bacterial Pathogens. Molecules 2017, 22, 2174.

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