Azole resistance in Aspergillus flavus and associated fitness cost
Background The resistance of Aspergillus flavus to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals ‐ CYP 51 A, B and C ‐ are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of...
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| Veröffentlicht in: | Mycoses 2024-07, Vol.67 (7), p.e13766-n/a |
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| creator | Djenontin, Elie Debourgogne, Anne Mousavi, Bita Delhaes, Laurence Cornet, Muriel Valsecchi, Isabel Adebo, Makiath Guillot, Jacques Botterel, Françoise Dannaoui, Eric |
| description | Background
The resistance of Aspergillus flavus to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals ‐ CYP 51 A, B and C ‐ are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of resistant strains in vitro and in vivo is not yet understood.
Objectives
This study had 3 objectives. The first was to compare the sequences of CYP51 A, B and C in resistant and susceptible strains of A. flavus. The second was to look for the existence of a fitness cost associated with resistance. The third was to evaluate the activity of voriconazole and posaconazole on resistant strains in the Galleria mellonella model.
Methods
The CYP51 A, B and C sequences of seven resistant strains with those of four susceptible strains are compared. Fitness costs were assessed by growing the strains in RPMI medium and testing their virulence in G. mellonella larvae. In addition, G. mellonella larvae infected with strains of A. flavus were treated with voriconazole and posaconazole.
Results
In the CYP51A sequences, we found the A91T, C708T and A1296T nucleotide substitutions only in the resistant strains. The resistant strains showed a fitness cost with reduced in vitro growth and reduced virulence in G. mellonella. In vivo resistance to posaconazole is confirmed in a strain with the highest MIC for this antifungal agent.
Conclusions
These results allow to conclude that some substitutions in CYP51 genes, in particular CYP51A, contribute to resistance to azole drugs in A. flavus. The study of the relationship between drug dosage and treatment duration with resistance and the reduction of fitness costs in resistant strains is a major perspective of this study. This work could help to establish recommendations for the treatment of infections with resistant strains of A. flavus. |
| doi_str_mv | 10.1111/myc.13766 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3080636155</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3085295038</sourcerecordid><originalsourceid>FETCH-LOGICAL-c2436-42d46f0701e76ba1e6fd26f06efe690504c26de9cb36ed6e43f356c7bb42d543</originalsourceid><addsrcrecordid>eNp10D1PwzAQBmALgWgpDPwBFIkFhrR2nJybsVR8SUUsXZgsx7kgV2lScgmo_HpcUhiQ8HKS9dyr08vYueBj4d9kvbVjIRXAARuKWKYhT7g6ZEOeShmqmKsBOyFacS5UGsExG8iUc5VEMGQ3s8-6xKBBctSaymLgqmBGG2xeXVl2FBSleffDVHlgiGrrTIt5ULi2QqLA1tSesqPClIRn-zliy7vb5fwhXDzfP85ni9BGsYQwjvIYCq64QAWZEQhFHvkPwAIh9RfHNoIcU5tJwBwwloVMwKos85tJLEfsqo_dNPVbh9TqtSOLZWkqrDvSkk85SBBJ4unlH7qqu6byx-1UEqUJl1Ovrntlm5qowUJvGrc2zVYLrne9at-r_u7V24t9YpetMf-VP0V6MOnBhytx-3-SfnqZ95FfPoWA4A</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3085295038</pqid></control><display><type>article</type><title>Azole resistance in Aspergillus flavus and associated fitness cost</title><source>Wiley Online Library - AutoHoldings Journals</source><source>MEDLINE</source><creator>Djenontin, Elie ; Debourgogne, Anne ; Mousavi, Bita ; Delhaes, Laurence ; Cornet, Muriel ; Valsecchi, Isabel ; Adebo, Makiath ; Guillot, Jacques ; Botterel, Françoise ; Dannaoui, Eric</creator><creatorcontrib>Djenontin, Elie ; Debourgogne, Anne ; Mousavi, Bita ; Delhaes, Laurence ; Cornet, Muriel ; Valsecchi, Isabel ; Adebo, Makiath ; Guillot, Jacques ; Botterel, Françoise ; Dannaoui, Eric</creatorcontrib><description>Background
The resistance of Aspergillus flavus to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals ‐ CYP 51 A, B and C ‐ are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of resistant strains in vitro and in vivo is not yet understood.
Objectives
This study had 3 objectives. The first was to compare the sequences of CYP51 A, B and C in resistant and susceptible strains of A. flavus. The second was to look for the existence of a fitness cost associated with resistance. The third was to evaluate the activity of voriconazole and posaconazole on resistant strains in the Galleria mellonella model.
Methods
The CYP51 A, B and C sequences of seven resistant strains with those of four susceptible strains are compared. Fitness costs were assessed by growing the strains in RPMI medium and testing their virulence in G. mellonella larvae. In addition, G. mellonella larvae infected with strains of A. flavus were treated with voriconazole and posaconazole.
Results
In the CYP51A sequences, we found the A91T, C708T and A1296T nucleotide substitutions only in the resistant strains. The resistant strains showed a fitness cost with reduced in vitro growth and reduced virulence in G. mellonella. In vivo resistance to posaconazole is confirmed in a strain with the highest MIC for this antifungal agent.
Conclusions
These results allow to conclude that some substitutions in CYP51 genes, in particular CYP51A, contribute to resistance to azole drugs in A. flavus. The study of the relationship between drug dosage and treatment duration with resistance and the reduction of fitness costs in resistant strains is a major perspective of this study. This work could help to establish recommendations for the treatment of infections with resistant strains of A. flavus.</description><identifier>ISSN: 0933-7407</identifier><identifier>ISSN: 1439-0507</identifier><identifier>EISSN: 1439-0507</identifier><identifier>DOI: 10.1111/myc.13766</identifier><identifier>PMID: 39007526</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Animals ; Antifungal Agents - pharmacology ; Aspergillosis - drug therapy ; Aspergillosis - microbiology ; Aspergillus flavus ; Aspergillus flavus - drug effects ; Aspergillus flavus - genetics ; Azoles - pharmacology ; CYP51 ; Cytochrome P-450 Enzyme System - genetics ; Disease Models, Animal ; Drug development ; Drug resistance ; Drug Resistance, Fungal - genetics ; fitness cost ; Fungal Proteins - genetics ; Galleria mellonella ; Genetic Fitness ; Larva - microbiology ; Microbial Sensitivity Tests ; Moths - microbiology ; Posaconazole ; Reproductive fitness ; resistance ; Triazoles - pharmacology ; Virulence ; Voriconazole ; Voriconazole - pharmacology</subject><ispartof>Mycoses, 2024-07, Vol.67 (7), p.e13766-n/a</ispartof><rights>2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd</rights><rights>2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2436-42d46f0701e76ba1e6fd26f06efe690504c26de9cb36ed6e43f356c7bb42d543</cites><orcidid>0000-0003-3577-6979</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fmyc.13766$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fmyc.13766$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39007526$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Djenontin, Elie</creatorcontrib><creatorcontrib>Debourgogne, Anne</creatorcontrib><creatorcontrib>Mousavi, Bita</creatorcontrib><creatorcontrib>Delhaes, Laurence</creatorcontrib><creatorcontrib>Cornet, Muriel</creatorcontrib><creatorcontrib>Valsecchi, Isabel</creatorcontrib><creatorcontrib>Adebo, Makiath</creatorcontrib><creatorcontrib>Guillot, Jacques</creatorcontrib><creatorcontrib>Botterel, Françoise</creatorcontrib><creatorcontrib>Dannaoui, Eric</creatorcontrib><title>Azole resistance in Aspergillus flavus and associated fitness cost</title><title>Mycoses</title><addtitle>Mycoses</addtitle><description>Background
The resistance of Aspergillus flavus to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals ‐ CYP 51 A, B and C ‐ are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of resistant strains in vitro and in vivo is not yet understood.
Objectives
This study had 3 objectives. The first was to compare the sequences of CYP51 A, B and C in resistant and susceptible strains of A. flavus. The second was to look for the existence of a fitness cost associated with resistance. The third was to evaluate the activity of voriconazole and posaconazole on resistant strains in the Galleria mellonella model.
Methods
The CYP51 A, B and C sequences of seven resistant strains with those of four susceptible strains are compared. Fitness costs were assessed by growing the strains in RPMI medium and testing their virulence in G. mellonella larvae. In addition, G. mellonella larvae infected with strains of A. flavus were treated with voriconazole and posaconazole.
Results
In the CYP51A sequences, we found the A91T, C708T and A1296T nucleotide substitutions only in the resistant strains. The resistant strains showed a fitness cost with reduced in vitro growth and reduced virulence in G. mellonella. In vivo resistance to posaconazole is confirmed in a strain with the highest MIC for this antifungal agent.
Conclusions
These results allow to conclude that some substitutions in CYP51 genes, in particular CYP51A, contribute to resistance to azole drugs in A. flavus. The study of the relationship between drug dosage and treatment duration with resistance and the reduction of fitness costs in resistant strains is a major perspective of this study. This work could help to establish recommendations for the treatment of infections with resistant strains of A. flavus.</description><subject>Animals</subject><subject>Antifungal Agents - pharmacology</subject><subject>Aspergillosis - drug therapy</subject><subject>Aspergillosis - microbiology</subject><subject>Aspergillus flavus</subject><subject>Aspergillus flavus - drug effects</subject><subject>Aspergillus flavus - genetics</subject><subject>Azoles - pharmacology</subject><subject>CYP51</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Disease Models, Animal</subject><subject>Drug development</subject><subject>Drug resistance</subject><subject>Drug Resistance, Fungal - genetics</subject><subject>fitness cost</subject><subject>Fungal Proteins - genetics</subject><subject>Galleria mellonella</subject><subject>Genetic Fitness</subject><subject>Larva - microbiology</subject><subject>Microbial Sensitivity Tests</subject><subject>Moths - microbiology</subject><subject>Posaconazole</subject><subject>Reproductive fitness</subject><subject>resistance</subject><subject>Triazoles - pharmacology</subject><subject>Virulence</subject><subject>Voriconazole</subject><subject>Voriconazole - pharmacology</subject><issn>0933-7407</issn><issn>1439-0507</issn><issn>1439-0507</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp10D1PwzAQBmALgWgpDPwBFIkFhrR2nJybsVR8SUUsXZgsx7kgV2lScgmo_HpcUhiQ8HKS9dyr08vYueBj4d9kvbVjIRXAARuKWKYhT7g6ZEOeShmqmKsBOyFacS5UGsExG8iUc5VEMGQ3s8-6xKBBctSaymLgqmBGG2xeXVl2FBSleffDVHlgiGrrTIt5ULi2QqLA1tSesqPClIRn-zliy7vb5fwhXDzfP85ni9BGsYQwjvIYCq64QAWZEQhFHvkPwAIh9RfHNoIcU5tJwBwwloVMwKos85tJLEfsqo_dNPVbh9TqtSOLZWkqrDvSkk85SBBJ4unlH7qqu6byx-1UEqUJl1Ovrntlm5qowUJvGrc2zVYLrne9at-r_u7V24t9YpetMf-VP0V6MOnBhytx-3-SfnqZ95FfPoWA4A</recordid><startdate>202407</startdate><enddate>202407</enddate><creator>Djenontin, Elie</creator><creator>Debourgogne, Anne</creator><creator>Mousavi, Bita</creator><creator>Delhaes, Laurence</creator><creator>Cornet, Muriel</creator><creator>Valsecchi, Isabel</creator><creator>Adebo, Makiath</creator><creator>Guillot, Jacques</creator><creator>Botterel, Françoise</creator><creator>Dannaoui, Eric</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>M7N</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3577-6979</orcidid></search><sort><creationdate>202407</creationdate><title>Azole resistance in Aspergillus flavus and associated fitness cost</title><author>Djenontin, Elie ; Debourgogne, Anne ; Mousavi, Bita ; Delhaes, Laurence ; Cornet, Muriel ; Valsecchi, Isabel ; Adebo, Makiath ; Guillot, Jacques ; Botterel, Françoise ; Dannaoui, Eric</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2436-42d46f0701e76ba1e6fd26f06efe690504c26de9cb36ed6e43f356c7bb42d543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Antifungal Agents - pharmacology</topic><topic>Aspergillosis - drug therapy</topic><topic>Aspergillosis - microbiology</topic><topic>Aspergillus flavus</topic><topic>Aspergillus flavus - drug effects</topic><topic>Aspergillus flavus - genetics</topic><topic>Azoles - pharmacology</topic><topic>CYP51</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Disease Models, Animal</topic><topic>Drug development</topic><topic>Drug resistance</topic><topic>Drug Resistance, Fungal - genetics</topic><topic>fitness cost</topic><topic>Fungal Proteins - genetics</topic><topic>Galleria mellonella</topic><topic>Genetic Fitness</topic><topic>Larva - microbiology</topic><topic>Microbial Sensitivity Tests</topic><topic>Moths - microbiology</topic><topic>Posaconazole</topic><topic>Reproductive fitness</topic><topic>resistance</topic><topic>Triazoles - pharmacology</topic><topic>Virulence</topic><topic>Voriconazole</topic><topic>Voriconazole - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Djenontin, Elie</creatorcontrib><creatorcontrib>Debourgogne, Anne</creatorcontrib><creatorcontrib>Mousavi, Bita</creatorcontrib><creatorcontrib>Delhaes, Laurence</creatorcontrib><creatorcontrib>Cornet, Muriel</creatorcontrib><creatorcontrib>Valsecchi, Isabel</creatorcontrib><creatorcontrib>Adebo, Makiath</creatorcontrib><creatorcontrib>Guillot, Jacques</creatorcontrib><creatorcontrib>Botterel, Françoise</creatorcontrib><creatorcontrib>Dannaoui, Eric</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><jtitle>Mycoses</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Djenontin, Elie</au><au>Debourgogne, Anne</au><au>Mousavi, Bita</au><au>Delhaes, Laurence</au><au>Cornet, Muriel</au><au>Valsecchi, Isabel</au><au>Adebo, Makiath</au><au>Guillot, Jacques</au><au>Botterel, Françoise</au><au>Dannaoui, Eric</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Azole resistance in Aspergillus flavus and associated fitness cost</atitle><jtitle>Mycoses</jtitle><addtitle>Mycoses</addtitle><date>2024-07</date><risdate>2024</risdate><volume>67</volume><issue>7</issue><spage>e13766</spage><epage>n/a</epage><pages>e13766-n/a</pages><issn>0933-7407</issn><issn>1439-0507</issn><eissn>1439-0507</eissn><abstract>Background
The resistance of Aspergillus flavus to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals ‐ CYP 51 A, B and C ‐ are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of resistant strains in vitro and in vivo is not yet understood.
Objectives
This study had 3 objectives. The first was to compare the sequences of CYP51 A, B and C in resistant and susceptible strains of A. flavus. The second was to look for the existence of a fitness cost associated with resistance. The third was to evaluate the activity of voriconazole and posaconazole on resistant strains in the Galleria mellonella model.
Methods
The CYP51 A, B and C sequences of seven resistant strains with those of four susceptible strains are compared. Fitness costs were assessed by growing the strains in RPMI medium and testing their virulence in G. mellonella larvae. In addition, G. mellonella larvae infected with strains of A. flavus were treated with voriconazole and posaconazole.
Results
In the CYP51A sequences, we found the A91T, C708T and A1296T nucleotide substitutions only in the resistant strains. The resistant strains showed a fitness cost with reduced in vitro growth and reduced virulence in G. mellonella. In vivo resistance to posaconazole is confirmed in a strain with the highest MIC for this antifungal agent.
Conclusions
These results allow to conclude that some substitutions in CYP51 genes, in particular CYP51A, contribute to resistance to azole drugs in A. flavus. The study of the relationship between drug dosage and treatment duration with resistance and the reduction of fitness costs in resistant strains is a major perspective of this study. This work could help to establish recommendations for the treatment of infections with resistant strains of A. flavus.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>39007526</pmid><doi>10.1111/myc.13766</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-3577-6979</orcidid></addata></record> |
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| source | Wiley Online Library - AutoHoldings Journals; MEDLINE |
| subjects | Animals Antifungal Agents - pharmacology Aspergillosis - drug therapy Aspergillosis - microbiology Aspergillus flavus Aspergillus flavus - drug effects Aspergillus flavus - genetics Azoles - pharmacology CYP51 Cytochrome P-450 Enzyme System - genetics Disease Models, Animal Drug development Drug resistance Drug Resistance, Fungal - genetics fitness cost Fungal Proteins - genetics Galleria mellonella Genetic Fitness Larva - microbiology Microbial Sensitivity Tests Moths - microbiology Posaconazole Reproductive fitness resistance Triazoles - pharmacology Virulence Voriconazole Voriconazole - pharmacology |
| title | Azole resistance in Aspergillus flavus and associated fitness cost |
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