Evaluation of the Mycobactericidal Effect of Thio-functionalized Carbohydrate Derivatives

Korycka-Machała, Małgorzata; Brzostek, Anna; Dziadek, Bożena; Kawka, Malwina; Popławski, Tomasz; Witczak, Zbigniew J.; Dziadek, Jarosław

doi:10.3390/molecules22050812

Cited by 21 publications

(31 citation statements)

References 48 publications

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“…It was recently reported that Mtb is sensitive to thio-functionalized carbohydrate derivatives, including thio-glycoside, thio-semicarbazone, aminothiazole and thiazoline [39]. Here, we found that the accumulation of mutations in the ppe51 gene affects the sensitivity of Mtb mutants to thio-glycoside (thio-disaccharide, T-6), which might be reversed by the introduction of an intact ppe51 gene into the mutants.…”

Section: Discussionmentioning

confidence: 70%

“…We have recently shown that thio-functionalized carbohydrate derivatives such as thioglycoside, thiosemicarbazone, aminothiadiazole and thiazoline present bactericidal activity against tubercle bacilli, inhibiting their growth at concentrations below 100 µM/CFU. At micromolar concentrations, these compounds were not active against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus [39]. Here, we applied the compound T-6, thio-disaccharide (1,6-anhydro-3-deoxy-4-S-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl-d-glycero-hexopyranos-2-ulose), at a concentration MIC 50 = 50 µM/CFU, to inhibit the growth of Mtb and to identify proteins involved in the uptake of T-6-like compounds.…”

Section: Selection Of T-6 Resistant Mutantsmentioning

confidence: 93%

“…Cultures were initiated at an optical density of 0.1 (OD 600 ) and supplemented with the tested chemical agents, at concentrations ranging from 1 to 0.01 mM. All thio-functionalized carbohydrate derivatives used in this work were synthesized and analyzed as described previously (see Supplementary Table S1) [39]. The viability assay was performed at 0, 24, 48, 72 and 96 h time points.…”

Section: Bacterial Strains and Growth Conditionsmentioning

confidence: 99%

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PPE51 Is Involved in the Uptake of Disaccharides by Mycobacterium tuberculosis

Korycka-Machała

Pawełczyk

Borówka

et al. 2020

Cells

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We have recently found that selected thio-disaccharides possess bactericidal effects against Mycobacterium tuberculosis but not against Escherichia coli or Staphylococcus aureus. Here, we selected spontaneous mutants displaying resistance against the investigated thio-glycoside. According to next-generation sequencing, four of six analyzed mutants which were resistant to high concentrations of the tested chemical carried nonsynonymous mutations in the gene encoding the PPE51 protein. The complementation of these mutants with an intact ppe51 gene returned their sensitivity to the wild-type level. The uptake of tritiated thio-glycoside was significantly more abundant in wild-type Mycobacterium tuberculosis compared to the strain carrying the mutated ppe51 gene. The ppe51 mutations or CRISPR-Cas9-mediated downregulation of PPE51 expression affected the growth of mutant strains on minimal media supplemented with disaccharides (maltose or lactose) but not with glycerol or glucose as the sole carbon and energy source. Taking the above into account, we postulate that PPE51 participates in the uptake of disaccharides by tubercle bacilli.

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Section: Discussionmentioning

confidence: 70%

Section: Selection Of T-6 Resistant Mutantsmentioning

confidence: 93%

Section: Bacterial Strains and Growth Conditionsmentioning

confidence: 99%

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PPE51 Is Involved in the Uptake of Disaccharides by Mycobacterium tuberculosis

Korycka-Machała

Pawełczyk

Borówka

et al. 2020

Cells

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“…Synthetic thiosugars are effective inhibitors of numerous cellular enzyme pathways. Besides, numerous studies have shown their significant antimicrobial, antiviral, antithrombotic, and anticancer potential [ 33 , 34 , 35 , 36 ]. Therefore, increasingly sulfur derivatives of carbohydrates are used for the synthesis of new pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

8-Hydroxyquinoline Glycoconjugates Containing Sulfur at the Sugar Anomeric Position—Synthesis and Preliminary Evaluation of Their Cytotoxicity

et al. 2020

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One of the main factors limiting the effectiveness of many drugs is the difficulty of their delivery to their target site in the cell and achieving the desired therapeutic dose. Moreover, the accumulation of the drug in healthy tissue can lead to serious side effects. The way to improve the selectivity of a drug to the cancer cells seems to be its conjugation with a sugar molecule, which should facilitate its selective transport through GLUT transporters (glucose transporters), whose overexpression is seen in some types of cancer. This was the idea behind the synthesis of 8-hydroxyquinoline (8-HQ) derivative glycoconjugates, for which 1-thiosugar derivatives were used as sugar moiety donors. It was expected that the introduction of a sulfur atom instead of an oxygen atom into the anomeric position of the sugar would increase the stability of the obtained glycoconjugates against untimely hydrolytic cleavage. The anticancer activity of new compounds was determined based on the results of the MTT cytotoxicity tests. Because of the assumption that the activity of this type of compounds was based on metal ion chelation, the effect of the addition of copper ions on cell proliferation was tested for some of them. It turned out that cancer cells treated with glycoconjugates in the presence of Cu2+ had a much slower growth rate compared to cells treated with free glycoconjugates in the absence of copper. The highest cytotoxic activity of the compounds was observed against the MCF-7 cell line.

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“…Particular attention has been given to antitubercolosis and antifungal derivatives. New promising antimycobacterial candidates emerged among a new set of carbohydrate derivatives studied by Korycka-Machala et al [ 6 ]. Starting from the consideration that sugars with heteroatoms other than oxygen have attained considerable importance in glycobiology and in drug design due to their resistance to enzymes such as glycosidases, phosphorylases and glycosyltransferases, the authors screened a set of 21 thio-functionalized carbohydrate derivatives against acid-fast Mycobacterium tuberculosis (Mtb) and several other bacteria.…”

mentioning

confidence: 99%