Serveur d'exploration sur la rapamycine et les champignons

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Rapamycin exerts antifungal activity in vitro and in vivo against Mucor circinelloides via FKBP12-dependent inhibition of Tor.

Identifieur interne : 001135 ( Main/Exploration ); précédent : 001134; suivant : 001136

Rapamycin exerts antifungal activity in vitro and in vivo against Mucor circinelloides via FKBP12-dependent inhibition of Tor.

Auteurs : Robert J. Bastidas [États-Unis] ; Cecelia A. Shertz ; Soo Chan Lee ; Joseph Heitman ; Maria E. Cardenas

Source :

RBID : pubmed:22210828

Descripteurs français

English descriptors

Abstract

The zygomycete Mucor circinelloides is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in M. circinelloides are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12-encoding gene, fkbA, also conferred rapamycin and FK506 resistance. Expression of M. circinelloides FKBP12 (McFKBP12) complemented a Saccharomyces cerevisiae mutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of the McTor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance in S. cerevisiae, and McFKBP12 interacted in a rapamycin-dependent fashion with the McTor FRB domain in a yeast two-hybrid assay, validating McFKBP12 and McTor as conserved targets of rapamycin. We showed that in vitro, rapamycin exhibited potent growth inhibitory activity against M. circinelloides. In a Galleria mellonella model of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis.

DOI: 10.1128/EC.05284-11
PubMed: 22210828
PubMed Central: PMC3294450


Affiliations:


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Le document en format XML

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<term>Fungal Proteins (genetics)</term>
<term>Fungal Proteins (metabolism)</term>
<term>Genetic Complementation Test (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Immunosuppressive Agents (pharmacology)</term>
<term>Larva (drug effects)</term>
<term>Larva (microbiology)</term>
<term>Moths (drug effects)</term>
<term>Moths (microbiology)</term>
<term>Mucor (drug effects)</term>
<term>Mucor (genetics)</term>
<term>Mucor (metabolism)</term>
<term>Mutation (MeSH)</term>
<term>Phylogeny (MeSH)</term>
<term>Protein Binding (MeSH)</term>
<term>Saccharomyces cerevisiae (genetics)</term>
<term>Saccharomyces cerevisiae (metabolism)</term>
<term>Sirolimus (pharmacology)</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
<term>TOR Serine-Threonine Kinases (genetics)</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
<term>Tacrolimus (pharmacology)</term>
<term>Tacrolimus Binding Protein 1A (genetics)</term>
<term>Tacrolimus Binding Protein 1A (metabolism)</term>
<term>Transfection (MeSH)</term>
<term>Two-Hybrid System Techniques (MeSH)</term>
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<term>Animaux (MeSH)</term>
<term>Antifongiques (pharmacologie)</term>
<term>Humains (MeSH)</term>
<term>Immunosuppresseurs (pharmacologie)</term>
<term>Larve (effets des médicaments et des substances chimiques)</term>
<term>Larve (microbiologie)</term>
<term>Liaison aux protéines (MeSH)</term>
<term>Mucor (effets des médicaments et des substances chimiques)</term>
<term>Mucor (génétique)</term>
<term>Mucor (métabolisme)</term>
<term>Mutation (MeSH)</term>
<term>Papillons de nuit (effets des médicaments et des substances chimiques)</term>
<term>Papillons de nuit (microbiologie)</term>
<term>Phylogenèse (MeSH)</term>
<term>Protéine 1A de liaison au tacrolimus (génétique)</term>
<term>Protéine 1A de liaison au tacrolimus (métabolisme)</term>
<term>Protéines fongiques (génétique)</term>
<term>Protéines fongiques (métabolisme)</term>
<term>Résistance des champignons aux médicaments (effets des médicaments et des substances chimiques)</term>
<term>Saccharomyces cerevisiae (génétique)</term>
<term>Saccharomyces cerevisiae (métabolisme)</term>
<term>Sirolimus (pharmacologie)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Sérine-thréonine kinases TOR (génétique)</term>
<term>Sérine-thréonine kinases TOR (métabolisme)</term>
<term>Tacrolimus (pharmacologie)</term>
<term>Techniques de double hybride (MeSH)</term>
<term>Test de complémentation (MeSH)</term>
<term>Transfection (MeSH)</term>
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<term>TOR Serine-Threonine Kinases</term>
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<term>Fungal Proteins</term>
<term>TOR Serine-Threonine Kinases</term>
<term>Tacrolimus Binding Protein 1A</term>
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<term>Fungal Proteins</term>
<term>TOR Serine-Threonine Kinases</term>
<term>Tacrolimus Binding Protein 1A</term>
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<term>Antifungal Agents</term>
<term>Immunosuppressive Agents</term>
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<term>Tacrolimus</term>
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<term>Sérine-thréonine kinases TOR</term>
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<term>Larva</term>
<term>Moths</term>
<term>Mucor</term>
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<term>Larve</term>
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<term>Papillons de nuit</term>
<term>Résistance des champignons aux médicaments</term>
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<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>Mucor</term>
<term>Saccharomyces cerevisiae</term>
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<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Mucor</term>
<term>Protéine 1A de liaison au tacrolimus</term>
<term>Protéines fongiques</term>
<term>Saccharomyces cerevisiae</term>
<term>Sérine-thréonine kinases TOR</term>
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<term>Mucor</term>
<term>Saccharomyces cerevisiae</term>
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<term>Larve</term>
<term>Papillons de nuit</term>
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<keywords scheme="MESH" qualifier="microbiology" xml:lang="en">
<term>Larva</term>
<term>Moths</term>
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<term>Mucor</term>
<term>Protéine 1A de liaison au tacrolimus</term>
<term>Protéines fongiques</term>
<term>Saccharomyces cerevisiae</term>
<term>Sérine-thréonine kinases TOR</term>
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<term>Genetic Complementation Test</term>
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<div type="abstract" xml:lang="en">The zygomycete Mucor circinelloides is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in M. circinelloides are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12-encoding gene, fkbA, also conferred rapamycin and FK506 resistance. Expression of M. circinelloides FKBP12 (McFKBP12) complemented a Saccharomyces cerevisiae mutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of the McTor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance in S. cerevisiae, and McFKBP12 interacted in a rapamycin-dependent fashion with the McTor FRB domain in a yeast two-hybrid assay, validating McFKBP12 and McTor as conserved targets of rapamycin. We showed that in vitro, rapamycin exhibited potent growth inhibitory activity against M. circinelloides. In a Galleria mellonella model of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis.</div>
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<AbstractText>The zygomycete Mucor circinelloides is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in M. circinelloides are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12-encoding gene, fkbA, also conferred rapamycin and FK506 resistance. Expression of M. circinelloides FKBP12 (McFKBP12) complemented a Saccharomyces cerevisiae mutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of the McTor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance in S. cerevisiae, and McFKBP12 interacted in a rapamycin-dependent fashion with the McTor FRB domain in a yeast two-hybrid assay, validating McFKBP12 and McTor as conserved targets of rapamycin. We showed that in vitro, rapamycin exhibited potent growth inhibitory activity against M. circinelloides. In a Galleria mellonella model of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis.</AbstractText>
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<ForeName>Soo Chan</ForeName>
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