Publications by authors named "Dana Logviniuk"

3 Publications

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Azide-Functionalized Derivatives of the Virulence-Associated Sugar Pseudaminic Acid: Chiral Pool Synthesis and Labeling of Bacteria.

Chemistry 2021 Mar 26. Epub 2021 Mar 26.

Tel Aviv University Raymond and Beverly Sackler Faculty of Exact Sciences, Organic Chemistry, ISRAEL.

Pseudaminic acid (Pse) is a significant prokaryotic monosaccharide found in important Gram-negative and Gram-positive bacteria. This unique sugar serves as a component of cell-surface-associated glycans or glycoproteins and is associated with their virulence. We report the synthesis of azidoacetamido-functionalized Pse derivatives as part of a search for Pse-derived metabolic labeling reagents. The synthesis was initiated with D-glucose (Glc), which served as a cost-effective chiral pool starting material. Key synthetic steps involve the conversion of C1 of Glc into the terminal methyl group of Pse, and inverting deoxyaminations at C3 and C5 of Glc followed by backbone elongation with a three-carbon unit using the Barbier reaction. Metabolic labeling experiments revealed that, of the four Pse derivatives, ester-protected C5 azidoacetamido-Pse successfully labeled cells of Pse-expressing Gram-positive and Gram-negative strains. No labeling was observed in cells of non-Pse-expressing strains. The ester-protected and C5 azidoacetamido-functionalized Pse is thus a useful reagent for the identification of bacteria expressing this unique virulence-associated nonulosonic acid.
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http://dx.doi.org/10.1002/chem.202100443DOI Listing
March 2021

Design Guidelines for Cationic Pillar[n]arenes that Prevent Biofilm Formation by Gram-Positive Pathogens.

ACS Infect Dis 2021 03 3;7(3):579-585. Epub 2021 Mar 3.

School of Chemistry, Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.

Bacterial biofilms are a major threat to human health, causing persistent infections that lead to millions of fatalities worldwide every year. Biofilms also cause billions of dollars of damage annually by interfering with industrial processes. Recently, cationic pillararenes were found to be potent inhibitors of biofilm formation in Gram-positive bacteria. To identify the structural features of pillararenes that result in antibiofilm activity, we evaluated the activity of 16 cationic pillar[5]arene derivatives including that of the first cationic water-soluble pillar[5]arene-based rotaxane. Twelve of the derivatives were potent inhibitors of biofilm formation by Gram-positive pathogens. Structure activity analyses of our pillararene derivatives indicated that positively charged head groups are critical for the observed antibiofilm activity. Although certain changes in the lipophilicity of the substituents on the positively charged head groups are tolerated, dramatic elevation in the hydrophobicity of the substituents or an increase in steric bulk on these positive charges abolishes the antibiofilm activity. An increase in the overall positive charge from 10 to 20 did not affect the activity significantly, but pillararenes with 5 positive charges and 5 long alkyl chains had reduced activity. Surprisingly, the cavity of the pillar[n]arene is not essential for the observed activity, although the macrocyclic structure of the pillar[n]arene core, which facilitates the clustering of the positive charges, appears important. Interestingly, the compounds found to be efficient inhibitors of biofilm formation were nonhemolytic at concentrations that are ∼100-fold of their MBIC (the minimal concentration of a compound at which at least 50% inhibition of biofilm formation was observed compared to untreated cells). The structure-activity relationship guidelines established here pave the way for a rational design of potent cationic pillar[n]arene-based antibiofilm agents.
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http://dx.doi.org/10.1021/acsinfecdis.0c00662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041275PMC
March 2021

Serum Prevents Interactions between Antimicrobial Amphiphilic Aminoglycosides and Plasma Membranes.

ACS Infect Dis 2020 12 11;6(12):3212-3223. Epub 2020 Nov 11.

School of Chemistry, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.

Antimicrobial cationic amphiphiles have broad-spectrum activity, and microbes do not readily develop resistance to these agents, highlighting their clinical and industrial potential. Cationic amphiphiles perturb the integrity of membranes leading to cell death, and the lack of discrimination between microbial and mammalian plasma membranes is thought to be one of the main barriers of using these agents for the treatment of systemic infections. Here, we describe the synthesis and study of 20 antimicrobial cationic amphiphiles that are derivatives of the aminoglycoside nebramine with different numbers of alkyl chain ethers that differ in length and degree of unsaturation. We determined antifungal activities and evaluated hemoglobin release from red blood cells as a measure of membrane selectivity and analyzed how serum influences these activities. Microscopic images revealed morphological transformations of red blood cells from the normal double-disc shape to empty ghost cells upon treatment with the cationic amphiphiles. Antifungal activity, hemolysis, and morphological changes in red blood cells decreased as the percentage of serum in the culture medium was increased. In images of red blood cells treated with fluorescently labeled amphiphilic nebramine probes, the accumulation of the cationic amphiphiles in the membranes decreased as serum concentration increased. This suggests that, in addition to its known effect of preventing the deformability of red blood cells, serum prevents interactions between cationic amphiphiles and the plasma membrane. The results of this study indicate that biological activities of cationic amphiphiles are abrogated in serum. Thus, these agents are suitable for external and industrial uses but probably not for effective treatment of systemic infections.
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http://dx.doi.org/10.1021/acsinfecdis.0c00588DOI Listing
December 2020