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A New Pyrimidine Schiff Base with Selective Activities against Enterococcus faecalis and Gastric Adenocarcinoma.

ABSTRACT: Enterococcus faecalis is known as a significant nosocomial pathogen due to its natural resistance to many antibacterial drugs. Moreover, it was found that E. faecalis infection causes inflammation, production of reactive oxygen species, and DNA damage to human gastric cancer cells, which can induce cancer. In this study, we synthesized and tested the biological activity of a new Schiff base, 5-[(4-ethoxyphenyl)imino]methyl-N-(4-fluorophenyl)-6-methyl-2-phenylpyrimidin-4-amine (3), and compared its properties with an analogous amine (2). In the biological investigation, 3 was found to have antibacterial activity against E. faecalis 29212 and far better anticancer properties, especially against gastric adenocarcinoma (human Caucasian gastric adenocarcinoma), than 2. In addition, both derivatives were non-toxic to normal cells. It is worth mentioning that 3 could potentially inhibit cancer cell growth by inducing cell apoptosis. The results suggest that the presence of the -C=N- bond in the molecule of 3 increases its activity, indicating that 5-iminomethylpyrimidine could be a potent core for further drug discovery research.

SUBMITTER: Stolarczyk M

PROVIDER: S-EPMC8071423 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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A New Pyrimidine Schiff Base with Selective Activities against Enterococcus faecalis and Gastric Adenocarcinoma.

Stolarczyk Marcin M Wolska Aleksandra A Mikołajczyk Aleksandra A Bryndal Iwona I Cieplik Jerzy J Lis Tadeusz T Matera-Witkiewicz Agnieszka A

Molecules (Basel, Switzerland) 20210415 8

Enterococcus faecalis is known as a significant nosocomial pathogen due to its natural resistance to many antibacterial drugs. Moreover, it was found that E. faecalis infection causes inflammation, production of reactive oxygen species, and DNA damage to human gastric cancer cells, which can induce cancer. In this study, we synthesized and tested the biological activity of a new Schiff base, 5-[(4-ethoxyphenyl)imino]methyl-N-(4-fluorophenyl)-6-methyl-2-phenylpyrimidin-4-amin ...[more]

PMID: 33921108

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Project description:BackgroundThe pharmacological activities of the natural product isobavachalcone, such as antimicrobial activity, reverse transcriptase blockade, and antioxidant property have been extensively reported. Whereas, its antimicrobial and biofilm-inhibitory effects on clinical E. faecalis strains in China, along with its potential mechanisms, are still not fully clear. This research is intended to assess the in vitro antibacterial and anti-biofilm effects of isobavachalcone against clinical E. faecalis isolates sourced from China. Moreover, it further explores the potential target site of it within E. faecalis.ResultsIt was found that the minimum inhibitory concentrations (MICs) of isobavachalcone ranged from 6.25 to 12.5 µM against 220 E. faecalis clinical strains obtained from a tertiary hospital in China. The antibiofilm activity of it with sub-MIC concentration ( 1/2 × MIC ) against the biofilm formation of E. faecalis was demonstrated and Time -killing curve assay revealed the quick bactericidal effect of isobavachalcone against E. faecalis planktonic cells. However, no synergetic bactericidal activity of isobavachalcone co-administered with vancomycin, or ampicillin was observed for eradicating the biofilm. Moreover, isobavachalcone-resistant E. faecalis was isolated by in vitro induction of isobavachalcone, and whole genome sequencing was performed to determine the genetic mutations of ten functional proteins in isobavachalcone-resistant E. faecalis, including PurH and FlgJ, with the other eight proteins being related to cell wall or cell membrane biogenesis, DNA synthesis, and energy metabolism. In addition, molecular docking results indicate that there is a potential binding of isobavachalcone and PurH protein in E. faecalis.ConclusionThis research highlights the potential of isobavachalcone as a potent antibacterial agent against E. faecalis clinical isolates, capable of significantly inhibiting biofilm formation at sub-MIC concentrations. PurH protein in E. faecalis might serve as a potential target of isobavachalcone and the specific action mechanism of isobavachalcone needs further study.

Project description:Maltose and maltodextrins are formed during the degradation of starch or glycogen. Maltodextrins are composed of a mixture of maltooligosaccharides formed by α-1,4- but also some α-1,6-linked glucosyl residues. The α-1,6-linked glucosyl residues are derived from branching points in the polysaccharides. In Enterococcus faecalis, maltotriose is mainly transported and phosphorylated by a phosphoenolpyruvate:carbohydrate phosphotransferase system. The formed maltotriose-6″-phosphate is intracellularly dephosphorylated by a specific phosphatase, MapP. In contrast, maltotetraose and longer maltooligosaccharides up to maltoheptaose are taken up without phosphorylation via the ATP binding cassette transporter MdxEFG-MsmX. We show that the maltose-producing maltodextrin hydrolase MmdH (GenBank accession no. EFT41964) in strain JH2-2 catalyzes the first catabolic step of α-1,4-linked maltooligosaccharides. The purified enzyme converts even-numbered α-1,4-linked maltooligosaccharides (maltotetraose, etc.) into maltose and odd-numbered (maltotriose, etc.) into maltose and glucose. Inactivation of mmdH therefore prevents the growth of E. faecalis on maltooligosaccharides ranging from maltotriose to maltoheptaose. Surprisingly, MmdH also functions as a maltogenic α-1,6-glucosidase, because it converts the maltotriose isomer isopanose into maltose and glucose. In addition, E. faecalis contains a glucose-producing α-1,6-specific maltodextrin hydrolase (GenBank accession no. EFT41963, renamed GmdH). This enzyme converts panose, another maltotriose isomer, into glucose and maltose. A gmdH mutant had therefore lost the capacity to grow on panose. The genes mmdH and gmdH are organized in an operon together with GenBank accession no. EFT41962 (renamed mmgT). Purified MmgT transfers glucosyl residues from one α-1,4-linked maltooligosaccharide molecule to another. For example, it catalyzes the disproportionation of maltotriose by transferring a glucosyl residue to another maltotriose molecule, thereby forming maltotetraose and maltose together with a small amount of maltopentaose.IMPORTANCE The utilization of maltodextrins by Enterococcus faecalis has been shown to increase the virulence of this nosocomial pathogen. However, little is known about how this organism catabolizes maltodextrins. We identified two enzymes involved in the metabolism of various α-1,4- and α-1,6-linked maltooligosaccharides. We found that one of them functions as a maltose-producing α-glucosidase with relaxed linkage specificity (α-1,4 and α-1,6) and exo- and endoglucosidase activities. A third enzyme, which resembles amylomaltase, exclusively transfers glucosyl residues from one maltooligosaccharide molecule to another. Similar enzymes are present in numerous other Firmicutes, such as streptococci and lactobacilli, suggesting that these organisms follow the same maltose degradation pathway as E. faecalis.

Dataset Information

A New Pyrimidine Schiff Base with Selective Activities against Enterococcus faecalis and Gastric Adenocarcinoma.

Publications

A New Pyrimidine Schiff Base with Selective Activities against <i>Enterococcus faecalis</i> and Gastric Adenocarcinoma.

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