Screening and characterisation of antimicrobial properties of semisynthetic betulin derivatives

S Haque (Corresponding Author), D A Nawrot (Corresponding Author), Sami Alakurtti, L Ghemtio, J Yli-Kauhaluoma, P Tammela (Corresponding Author)

    Research output: Contribution to journalArticleScientificpeer-review

    15 Citations (Scopus)

    Abstract

    Betulin (lup-20(29)-ene-3ß, 28-diol) is a naturally occurring triterpene, which is found in substantial amounts from the outer bark of birch trees. A library of 51 structurally diverse semisynthetic betulin derivatives was screened against five bacterial strains, Enterobacter aerogenes, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus and a fungal strain Candida albicans, using broth microdilution assays. Primary antimicrobial screening at 50 µM concentration led to the identification of five compounds showing antimicrobial properties (inhibition of growth by >70% against one or more microbial strains). According to the dose-response results, 28-O-(N-acetylanthraniloyl)betulin (compound 5) was the most active, showing MIC90 of 6.25 µM against two Gram-positive bacteria, E. faecalis and S. aureus. However, the activity of this compound was affected by albumin binding, which was demonstrated by the loss of activity in a host-pathogen co-culture assay as well as in the antibacterial assay in the presence of increased concentration of albumin. Furthermore, the effects on mammalian cells were evaluated by cytotoxicity assessment on hepatocyte cell culture after 24 h exposure to the compounds. Betulinic aldehyde (18), betulin-28-oxime ( 31) and hetero cycloadduct with acetoxy groups at carbon atoms 3 and 28 and ethyl substituent at the triazolo ring ( 43) displayed cytotoxicity towards hepatocytes, with IC50 values of 47, 25 and 16 mM, respectively. The IC50 value for 28-O-(N-acetylanthraniloyl)betulin (5) was 56 µM. The current study presents an insight into using betulin scaffold for developing derivatives with antibacterial potential, and furthermore the necessity of in-depth analysis of found actives through selectivity profiling and follow-up studies including in silico ADMET predictions
    Original languageEnglish
    Article numbere102696
    JournalPLoS ONE
    Volume9
    Issue number7
    DOIs
    Publication statusPublished - 2014
    MoE publication typeA1 Journal article-refereed

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    betulin
    anti-infective properties
    Screening
    chemical derivatives
    screening
    Derivatives
    Assays
    Enterococcus faecalis
    Cytotoxicity
    hepatocytes
    Inhibitory Concentration 50
    albumins
    inhibitory concentration 50
    Staphylococcus aureus
    cytotoxicity
    Hepatocytes
    Albumins
    assays
    Plant Bark
    Enterobacter aerogenes

    Cite this

    Haque, S., Nawrot, D. A., Alakurtti, S., Ghemtio, L., Yli-Kauhaluoma, J., & Tammela, P. (2014). Screening and characterisation of antimicrobial properties of semisynthetic betulin derivatives. PLoS ONE, 9(7), [e102696]. https://doi.org/10.1371/journal.pone.0102696
    Haque, S ; Nawrot, D A ; Alakurtti, Sami ; Ghemtio, L ; Yli-Kauhaluoma, J ; Tammela, P. / Screening and characterisation of antimicrobial properties of semisynthetic betulin derivatives. In: PLoS ONE. 2014 ; Vol. 9, No. 7.
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    title = "Screening and characterisation of antimicrobial properties of semisynthetic betulin derivatives",
    abstract = "Betulin (lup-20(29)-ene-3{\ss}, 28-diol) is a naturally occurring triterpene, which is found in substantial amounts from the outer bark of birch trees. A library of 51 structurally diverse semisynthetic betulin derivatives was screened against five bacterial strains, Enterobacter aerogenes, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus and a fungal strain Candida albicans, using broth microdilution assays. Primary antimicrobial screening at 50 µM concentration led to the identification of five compounds showing antimicrobial properties (inhibition of growth by >70{\%} against one or more microbial strains). According to the dose-response results, 28-O-(N-acetylanthraniloyl)betulin (compound 5) was the most active, showing MIC90 of 6.25 µM against two Gram-positive bacteria, E. faecalis and S. aureus. However, the activity of this compound was affected by albumin binding, which was demonstrated by the loss of activity in a host-pathogen co-culture assay as well as in the antibacterial assay in the presence of increased concentration of albumin. Furthermore, the effects on mammalian cells were evaluated by cytotoxicity assessment on hepatocyte cell culture after 24 h exposure to the compounds. Betulinic aldehyde (18), betulin-28-oxime ( 31) and hetero cycloadduct with acetoxy groups at carbon atoms 3 and 28 and ethyl substituent at the triazolo ring ( 43) displayed cytotoxicity towards hepatocytes, with IC50 values of 47, 25 and 16 mM, respectively. The IC50 value for 28-O-(N-acetylanthraniloyl)betulin (5) was 56 µM. The current study presents an insight into using betulin scaffold for developing derivatives with antibacterial potential, and furthermore the necessity of in-depth analysis of found actives through selectivity profiling and follow-up studies including in silico ADMET predictions",
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    Haque, S, Nawrot, DA, Alakurtti, S, Ghemtio, L, Yli-Kauhaluoma, J & Tammela, P 2014, 'Screening and characterisation of antimicrobial properties of semisynthetic betulin derivatives', PLoS ONE, vol. 9, no. 7, e102696. https://doi.org/10.1371/journal.pone.0102696

    Screening and characterisation of antimicrobial properties of semisynthetic betulin derivatives. / Haque, S (Corresponding Author); Nawrot, D A (Corresponding Author); Alakurtti, Sami; Ghemtio, L; Yli-Kauhaluoma, J; Tammela, P (Corresponding Author).

    In: PLoS ONE, Vol. 9, No. 7, e102696, 2014.

    Research output: Contribution to journalArticleScientificpeer-review

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    AB - Betulin (lup-20(29)-ene-3ß, 28-diol) is a naturally occurring triterpene, which is found in substantial amounts from the outer bark of birch trees. A library of 51 structurally diverse semisynthetic betulin derivatives was screened against five bacterial strains, Enterobacter aerogenes, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus and a fungal strain Candida albicans, using broth microdilution assays. Primary antimicrobial screening at 50 µM concentration led to the identification of five compounds showing antimicrobial properties (inhibition of growth by >70% against one or more microbial strains). According to the dose-response results, 28-O-(N-acetylanthraniloyl)betulin (compound 5) was the most active, showing MIC90 of 6.25 µM against two Gram-positive bacteria, E. faecalis and S. aureus. However, the activity of this compound was affected by albumin binding, which was demonstrated by the loss of activity in a host-pathogen co-culture assay as well as in the antibacterial assay in the presence of increased concentration of albumin. Furthermore, the effects on mammalian cells were evaluated by cytotoxicity assessment on hepatocyte cell culture after 24 h exposure to the compounds. Betulinic aldehyde (18), betulin-28-oxime ( 31) and hetero cycloadduct with acetoxy groups at carbon atoms 3 and 28 and ethyl substituent at the triazolo ring ( 43) displayed cytotoxicity towards hepatocytes, with IC50 values of 47, 25 and 16 mM, respectively. The IC50 value for 28-O-(N-acetylanthraniloyl)betulin (5) was 56 µM. The current study presents an insight into using betulin scaffold for developing derivatives with antibacterial potential, and furthermore the necessity of in-depth analysis of found actives through selectivity profiling and follow-up studies including in silico ADMET predictions

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