A prodrug approach to the use of coumarins as potential therapeutics for superficial mycoses
Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails that affect 20-25% of the world's population, with increasing incidence. Treatment of superficial mycoses, predominantly caused by dermatophytes, is by topical and/or oral regimens. New therapeutic options with improved efficacy and/or safety profiles are desirable. There is renewed interest in natural product-based antimicrobials as alternatives to conventional treatments, including the treatment of superficial mycoses. We investigated the potential of coumarins as dermatophyte-specific antifungal agents and describe for the first time their potential utility as topical antifungals for superficial mycoses using a prodrug approach. Here we demonstrate that an inactive coumarin glycone, esculin, is hydrolysed to the antifungal coumarin aglycone, esculetin by dermatophytes. Esculin is hydrolysed to esculetin β-glucosidases. We demonstrate that β-glucosidases are produced by dermatophytes as well as members of the dermal microbiota, and that this activity is sufficient to hydrolyse esculin to esculetin with concomitant antifungal activity. A β-glucosidase inhibitor (conduritol B epoxide), inhibited antifungal activity by preventing esculin hydrolysis. Esculin demonstrates good aqueous solubility (<6 g/l) and could be readily formulated and delivered topically as an inactive prodrug in a water-based gel or cream. This work demonstrates proof-of-principle for a therapeutic application of glycosylated coumarins as inactive prodrugs that could be converted to an active antifungal in situ. It is anticipated that this approach will be applicable to other coumarin glycones.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2013 |
|---|---|
| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
|---|---|
| Enthalten in: |
PloS one - 8(2013), 11 vom: 01., Seite e80760 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Mercer, Derry K [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
1Y1L18LQAF |
|---|
| Anmerkungen: |
Date Completed 26.08.2014 Date Revised 21.10.2021 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.1371/journal.pone.0080760 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM232916373 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM232916373 | ||
| 003 | DE-627 | ||
| 005 | 20231224094015.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2013 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1371/journal.pone.0080760 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0776.xml |
| 035 | |a (DE-627)NLM232916373 | ||
| 035 | |a (NLM)24260474 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Mercer, Derry K |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A prodrug approach to the use of coumarins as potential therapeutics for superficial mycoses |
| 264 | 1 | |c 2013 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 26.08.2014 | ||
| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails that affect 20-25% of the world's population, with increasing incidence. Treatment of superficial mycoses, predominantly caused by dermatophytes, is by topical and/or oral regimens. New therapeutic options with improved efficacy and/or safety profiles are desirable. There is renewed interest in natural product-based antimicrobials as alternatives to conventional treatments, including the treatment of superficial mycoses. We investigated the potential of coumarins as dermatophyte-specific antifungal agents and describe for the first time their potential utility as topical antifungals for superficial mycoses using a prodrug approach. Here we demonstrate that an inactive coumarin glycone, esculin, is hydrolysed to the antifungal coumarin aglycone, esculetin by dermatophytes. Esculin is hydrolysed to esculetin β-glucosidases. We demonstrate that β-glucosidases are produced by dermatophytes as well as members of the dermal microbiota, and that this activity is sufficient to hydrolyse esculin to esculetin with concomitant antifungal activity. A β-glucosidase inhibitor (conduritol B epoxide), inhibited antifungal activity by preventing esculin hydrolysis. Esculin demonstrates good aqueous solubility (<6 g/l) and could be readily formulated and delivered topically as an inactive prodrug in a water-based gel or cream. This work demonstrates proof-of-principle for a therapeutic application of glycosylated coumarins as inactive prodrugs that could be converted to an active antifungal in situ. It is anticipated that this approach will be applicable to other coumarin glycones | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Antifungal Agents |2 NLM | |
| 650 | 7 | |a Coumarins |2 NLM | |
| 650 | 7 | |a Drosophila Proteins |2 NLM | |
| 650 | 7 | |a Prodrugs |2 NLM | |
| 650 | 7 | |a Umbelliferones |2 NLM | |
| 650 | 7 | |a rudhira protein, Drosophila |2 NLM | |
| 650 | 7 | |a Esculin |2 NLM | |
| 650 | 7 | |a 1Y1L18LQAF |2 NLM | |
| 650 | 7 | |a coumarin |2 NLM | |
| 650 | 7 | |a A4VZ22K1WT |2 NLM | |
| 650 | 7 | |a beta-Glucosidase |2 NLM | |
| 650 | 7 | |a EC 3.2.1.21 |2 NLM | |
| 650 | 7 | |a esculetin |2 NLM | |
| 650 | 7 | |a SM2XD6V944 |2 NLM | |
| 700 | 1 | |a Robertson, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Wright, Kristine |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Lorna |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Shane |e verfasserin |4 aut | |
| 700 | 1 | |a Stewart, Colin S |e verfasserin |4 aut | |
| 700 | 1 | |a O Neil, Deborah A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t PloS one |d 2006 |g 8(2013), 11 vom: 01., Seite e80760 |w (DE-627)NLM167327399 |x 1932-6203 |7 nnns |
| 773 | 1 | 8 | |g volume:8 |g year:2013 |g number:11 |g day:01 |g pages:e80760 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1371/journal.pone.0080760 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 8 |j 2013 |e 11 |b 01 |h e80760 | ||