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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 (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.
Highlights
The emergence and spread of antimicrobial resistance among pathogenic bacteria represents a major global healthcare problem in the 21st century [1]
In order to assess some central drug-safety properties for the selenium agents (1–8 and ebselen), and bearing in mind that certain inorganic-selenium compounds such as selenite (SeO3 2− ) interact unfavourably with DNA, all relevant compounds were investigated for their possible mutagenic properties in vitro employing the microtiter Ames test [25,26,27,28,29]
Each experiment was performed in triplicate, and results were given in terms of mutagenic index (MI), which is the quotient of the number of revertant colonies induced in a test sample and the number of revertants in a negative control
Summary
The emergence and spread of antimicrobial resistance among pathogenic bacteria represents a major global healthcare problem in the 21st century [1]. A number of common pathogens are reported to develop resistances against virtually all types or classes of antibiotics [2]. Molecules 2017, 22, 2174 that pose a growing challenge for healthcare practitioners due to their antimicrobial resistance are referred as ESKAPE pathogens and include vancomycin-resistant enterococci (VRE), methicillin resistant. The acronym ESKAPE was first proposed by Rice et al in 2008 to emphasize the great capacity of these bacteria to “escape” from common antibacterial treatment through rapid acquisition or development of resistance determinants allowing them to tolerate the antimicrobial substance(s) [3,4,5,6]. Among ESKAPE pathogens, MRSA strains are the most prevalent Gram-positive bacteria, causing nosocomial infections throughout the world [8,9]
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