RapamycinFungusV1, Main, Exploration, bibRecord, 000377

Broad antifungal resistance mediated by RNAi-dependent epimutation in the basal human fungal pathogen Mucor circinelloides.

Identifieur interne : 000377 ( Main/Exploration ); précédent : 000376; suivant : 000378

Broad antifungal resistance mediated by RNAi-dependent epimutation in the basal human fungal pathogen Mucor circinelloides.

Auteurs : Zanetta Chang [États-Unis] ; R Blake Billmyre [États-Unis] ; Soo Chan Lee [États-Unis] ; Joseph Heitman [États-Unis]

Source :

PLoS genetics [ 1553-7404 ] ; 2019.

RBID : pubmed:30742617

Descripteurs français

KwdFr :
- ARN fongique (génétique), Acide orotique (analogues et dérivés), Acide orotique (pharmacologie), Antifongiques (pharmacologie), Gènes fongiques (MeSH), Humains (MeSH), Interférence par ARN (MeSH), Mucor (effets des médicaments et des substances chimiques), Mucor (génétique), Mucor (pathogénicité), Mucormycose (microbiologie), Mucormycose (traitement médicamenteux), Multirésistance des champignons aux médicaments (génétique), Mutation (MeSH), Orotate phosphoribosyltransferase (génétique), Orotine 5'-phosphate decarboxylase (génétique), Sirolimus (pharmacologie), Tacrolimus (pharmacologie), Épigenèse génétique (MeSH).
MESH :
- analogues et dérivés : Acide orotique.
- effets des médicaments et des substances chimiques : Mucor.
- génétique : ARN fongique, Mucor, Multirésistance des champignons aux médicaments, Orotate phosphoribosyltransferase, Orotine 5'-phosphate decarboxylase.
- microbiologie : Mucormycose.
- pathogénicité : Mucor.
- pharmacologie : Acide orotique, Antifongiques, Sirolimus, Tacrolimus.
- traitement médicamenteux : Mucormycose.
- Gènes fongiques, Humains, Interférence par ARN, Mutation, Épigenèse génétique.

English descriptors

KwdEn :
- Antifungal Agents (pharmacology), Drug Resistance, Multiple, Fungal (genetics), Epigenesis, Genetic (MeSH), Genes, Fungal (MeSH), Humans (MeSH), Mucor (drug effects), Mucor (genetics), Mucor (pathogenicity), Mucormycosis (drug therapy), Mucormycosis (microbiology), Mutation (MeSH), Orotate Phosphoribosyltransferase (genetics), Orotic Acid (analogs & derivatives), Orotic Acid (pharmacology), Orotidine-5'-Phosphate Decarboxylase (genetics), RNA Interference (MeSH), RNA, Fungal (genetics), Sirolimus (pharmacology), Tacrolimus (pharmacology).
MESH :
- chemical , analogs & derivatives : Orotic Acid.
- chemical , genetics : Orotate Phosphoribosyltransferase, Orotidine-5'-Phosphate Decarboxylase, RNA, Fungal.
- chemical , pharmacology : Antifungal Agents, Orotic Acid, Sirolimus, Tacrolimus.
- drug effects : Mucor.
- drug therapy : Mucormycosis.
- genetics : Drug Resistance, Multiple, Fungal, Mucor.
- microbiology : Mucormycosis.
- pathogenicity : Mucor.
- Epigenesis, Genetic, Genes, Fungal, Humans, Mutation, RNA Interference.

Abstract

Mucormycosis-an emergent, deadly fungal infection-is difficult to treat, in part because the causative species demonstrate broad clinical antifungal resistance. However, the mechanisms underlying drug resistance in these infections remain poorly understood. Our previous work demonstrated that one major agent of mucormycosis, Mucor circinelloides, can develop resistance to the antifungal agents FK506 and rapamycin through a novel, transient RNA interference-dependent mechanism known as epimutation. Epimutations silence the drug target gene and are selected by drug exposure; the target gene is re-expressed and sensitivity is restored following passage without drug. This silencing process involves generation of small RNA (sRNA) against the target gene via core RNAi pathway proteins. To further elucidate the role of epimutation in the broad antifungal resistance of Mucor, epimutants were isolated that confer resistance to another antifungal agent, 5-fluoroorotic acid (5-FOA). We identified epimutant strains that exhibit resistance to 5-FOA without mutations in PyrF or PyrG, enzymes which convert 5-FOA into the active toxic form. Using sRNA hybridization as well as sRNA library analysis, we demonstrate that these epimutants harbor sRNA against either pyrF or pyrG, and further show that this sRNA is lost after reversion to drug sensitivity. We conclude that epimutation is a mechanism capable of targeting multiple genes, enabling Mucor to develop resistance to a variety of antifungal agents. Elucidation of the role of RNAi in epimutation affords a fuller understanding of mucormycosis. Furthermore, it improves our understanding of fungal pathogenesis and adaptation to stresses, including the evolution of drug resistance.

DOI: 10.1371/journal.pgen.1007957
PubMed: 30742617
PubMed Central: PMC6386414

Affiliations:

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000345
to stream Main, to step Curation: 000345

Le document en format XML

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<term>Genes, Fungal (MeSH)</term>
<term>Humans (MeSH)</term>
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<term>Mucor (genetics)</term>
<term>Mucor (pathogenicity)</term>
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<term>Orotic Acid (analogs & derivatives)</term>
<term>Orotic Acid (pharmacology)</term>
<term>Orotidine-5'-Phosphate Decarboxylase (genetics)</term>
<term>RNA Interference (MeSH)</term>
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<term>Sirolimus (pharmacology)</term>
<term>Tacrolimus (pharmacology)</term>
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<term>Mucor (génétique)</term>
<term>Mucor (pathogénicité)</term>
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<term>Mucormycose (traitement médicamenteux)</term>
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<term>Orotine 5'-phosphate decarboxylase (génétique)</term>
<term>Sirolimus (pharmacologie)</term>
<term>Tacrolimus (pharmacologie)</term>
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<term>Orotidine-5'-Phosphate Decarboxylase</term>
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<front><div type="abstract" xml:lang="en">Mucormycosis-an emergent, deadly fungal infection-is difficult to treat, in part because the causative species demonstrate broad clinical antifungal resistance. However, the mechanisms underlying drug resistance in these infections remain poorly understood. Our previous work demonstrated that one major agent of mucormycosis, Mucor circinelloides, can develop resistance to the antifungal agents FK506 and rapamycin through a novel, transient RNA interference-dependent mechanism known as epimutation. Epimutations silence the drug target gene and are selected by drug exposure; the target gene is re-expressed and sensitivity is restored following passage without drug. This silencing process involves generation of small RNA (sRNA) against the target gene via core RNAi pathway proteins. To further elucidate the role of epimutation in the broad antifungal resistance of Mucor, epimutants were isolated that confer resistance to another antifungal agent, 5-fluoroorotic acid (5-FOA). We identified epimutant strains that exhibit resistance to 5-FOA without mutations in PyrF or PyrG, enzymes which convert 5-FOA into the active toxic form. Using sRNA hybridization as well as sRNA library analysis, we demonstrate that these epimutants harbor sRNA against either pyrF or pyrG, and further show that this sRNA is lost after reversion to drug sensitivity. We conclude that epimutation is a mechanism capable of targeting multiple genes, enabling Mucor to develop resistance to a variety of antifungal agents. Elucidation of the role of RNAi in epimutation affords a fuller understanding of mucormycosis. Furthermore, it improves our understanding of fungal pathogenesis and adaptation to stresses, including the evolution of drug resistance.</div>
</front>
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<Abstract><AbstractText>Mucormycosis-an emergent, deadly fungal infection-is difficult to treat, in part because the causative species demonstrate broad clinical antifungal resistance. However, the mechanisms underlying drug resistance in these infections remain poorly understood. Our previous work demonstrated that one major agent of mucormycosis, Mucor circinelloides, can develop resistance to the antifungal agents FK506 and rapamycin through a novel, transient RNA interference-dependent mechanism known as epimutation. Epimutations silence the drug target gene and are selected by drug exposure; the target gene is re-expressed and sensitivity is restored following passage without drug. This silencing process involves generation of small RNA (sRNA) against the target gene via core RNAi pathway proteins. To further elucidate the role of epimutation in the broad antifungal resistance of Mucor, epimutants were isolated that confer resistance to another antifungal agent, 5-fluoroorotic acid (5-FOA). We identified epimutant strains that exhibit resistance to 5-FOA without mutations in PyrF or PyrG, enzymes which convert 5-FOA into the active toxic form. Using sRNA hybridization as well as sRNA library analysis, we demonstrate that these epimutants harbor sRNA against either pyrF or pyrG, and further show that this sRNA is lost after reversion to drug sensitivity. We conclude that epimutation is a mechanism capable of targeting multiple genes, enabling Mucor to develop resistance to a variety of antifungal agents. Elucidation of the role of RNAi in epimutation affords a fuller understanding of mucormycosis. Furthermore, it improves our understanding of fungal pathogenesis and adaptation to stresses, including the evolution of drug resistance.</AbstractText>
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	Serveur d'exploration sur la rapamycine et les champignons
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Broad antifungal resistance mediated by RNAi-dependent epimutation in the basal human fungal pathogen Mucor circinelloides.

Broad antifungal resistance mediated by RNAi-dependent epimutation in the basal human fungal pathogen Mucor circinelloides.

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