The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum
The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment. is the most commonly isolated fungus in dermatophytosis. In , we identified TERG_07844, a gene encoding a previously uncharacterized pu...
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| Veröffentlicht in: | Antimicrobial agents and chemotherapy 2024-05, Vol.68 (5), p.e0160923-e0160923 |
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| creator | Ishii, Masaki Yamada, Tsuyoshi Ishikawa, Kazuki Ichinose, Koji Monod, Michel Ohata, Shinya |
| description | The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment.
is the most commonly isolated fungus in dermatophytosis. In
, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast
polyamine transport kinase 2 (Ptk2), and found that
Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both
and
, Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in
. Overexpression of
Pma1 (TrPma1) in
Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine-resistant dermatophytes. |
| doi_str_mv | 10.1128/aac.01609-23 |
| format | Article |
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is the most commonly isolated fungus in dermatophytosis. In
, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast
polyamine transport kinase 2 (Ptk2), and found that
Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both
and
, Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in
. Overexpression of
Pma1 (TrPma1) in
Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine-resistant dermatophytes.</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/aac.01609-23</identifier><identifier>PMID: 38567956</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>Antifungal Agents - pharmacology ; Arthrodermataceae - drug effects ; Arthrodermataceae - genetics ; Drug Resistance, Fungal - genetics ; Fungal Proteins - genetics ; Fungal Proteins - metabolism ; Mechanisms of Action: Physiological Effects ; Microbial Sensitivity Tests ; Mycology ; Phosphorylation ; Proton-Translocating ATPases - genetics ; Proton-Translocating ATPases - metabolism ; Saccharomyces cerevisiae - drug effects ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism ; Terbinafine - pharmacology</subject><ispartof>Antimicrobial agents and chemotherapy, 2024-05, Vol.68 (5), p.e0160923-e0160923</ispartof><rights>Copyright © 2024 Ishii et al.</rights><rights>Copyright © 2024 Ishii et al. 2024 Ishii et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a419t-a024f4354dfa372e09824c05b3be5c231bc488d7cf95f28160f2d682e064402e3</citedby><cites>FETCH-LOGICAL-a419t-a024f4354dfa372e09824c05b3be5c231bc488d7cf95f28160f2d682e064402e3</cites><orcidid>0000-0002-1394-5455 ; 0000-0003-0687-3147 ; 0000-0003-4333-4433</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11064548/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11064548/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38567956$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Groll, Andreas H.</contributor><creatorcontrib>Ishii, Masaki</creatorcontrib><creatorcontrib>Yamada, Tsuyoshi</creatorcontrib><creatorcontrib>Ishikawa, Kazuki</creatorcontrib><creatorcontrib>Ichinose, Koji</creatorcontrib><creatorcontrib>Monod, Michel</creatorcontrib><creatorcontrib>Ohata, Shinya</creatorcontrib><title>The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum</title><title>Antimicrobial agents and chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment.
is the most commonly isolated fungus in dermatophytosis. In
, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast
polyamine transport kinase 2 (Ptk2), and found that
Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both
and
, Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in
. Overexpression of
Pma1 (TrPma1) in
Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine-resistant dermatophytes.</description><subject>Antifungal Agents - pharmacology</subject><subject>Arthrodermataceae - drug effects</subject><subject>Arthrodermataceae - genetics</subject><subject>Drug Resistance, Fungal - genetics</subject><subject>Fungal Proteins - genetics</subject><subject>Fungal Proteins - metabolism</subject><subject>Mechanisms of Action: Physiological Effects</subject><subject>Microbial Sensitivity Tests</subject><subject>Mycology</subject><subject>Phosphorylation</subject><subject>Proton-Translocating ATPases - genetics</subject><subject>Proton-Translocating ATPases - metabolism</subject><subject>Saccharomyces cerevisiae - drug effects</subject><subject>Saccharomyces cerevisiae - genetics</subject><subject>Saccharomyces cerevisiae Proteins - genetics</subject><subject>Saccharomyces cerevisiae Proteins - metabolism</subject><subject>Terbinafine - pharmacology</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kTtPwzAURi0EoqWwMaOMIJHid50JoYqXVEGHMluO65CUxC52Auq_x6WlgoHJ17pHx_f6A-AUwSFCWFwppYcQcZilmOyBPoKZSDnL-D7oQ8h5SgWkPXAUwgLGO8vgIegRwfgoY7wPnmalSabtG06njULJUrXlp1olxpbKahOS1tXGr8tYJa3xeWVVUVmTVDaZ-UqXblmuWmcT3-W-a47BQaHqYE625wC83N3Oxg_p5Pn-cXwzSRVFWZsqiGlBCaPzQpERNnFmTDVkOckN05igXFMh5iNdZKzAIm5X4DkXEeSUQmzIAFxvvMsub8xcG9t6VculrxrlV9KpSv7t2KqUr-5DIhQVjIpoON8avHvvTGhlUwVt6lpZ47ogCSSIM8HwGr3coNq7ELwpdu8gKNcZyJiB_M5AYhLxiw2uQoPlwnXexq_4jz37vcdO_BMQ-QJF2I-B</recordid><startdate>20240502</startdate><enddate>20240502</enddate><creator>Ishii, Masaki</creator><creator>Yamada, Tsuyoshi</creator><creator>Ishikawa, Kazuki</creator><creator>Ichinose, Koji</creator><creator>Monod, Michel</creator><creator>Ohata, Shinya</creator><general>American Society for Microbiology</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1394-5455</orcidid><orcidid>https://orcid.org/0000-0003-0687-3147</orcidid><orcidid>https://orcid.org/0000-0003-4333-4433</orcidid></search><sort><creationdate>20240502</creationdate><title>The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum</title><author>Ishii, Masaki ; Yamada, Tsuyoshi ; Ishikawa, Kazuki ; Ichinose, Koji ; Monod, Michel ; Ohata, Shinya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a419t-a024f4354dfa372e09824c05b3be5c231bc488d7cf95f28160f2d682e064402e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Antifungal Agents - pharmacology</topic><topic>Arthrodermataceae - drug effects</topic><topic>Arthrodermataceae - genetics</topic><topic>Drug Resistance, Fungal - genetics</topic><topic>Fungal Proteins - genetics</topic><topic>Fungal Proteins - metabolism</topic><topic>Mechanisms of Action: Physiological Effects</topic><topic>Microbial Sensitivity Tests</topic><topic>Mycology</topic><topic>Phosphorylation</topic><topic>Proton-Translocating ATPases - genetics</topic><topic>Proton-Translocating ATPases - metabolism</topic><topic>Saccharomyces cerevisiae - drug effects</topic><topic>Saccharomyces cerevisiae - genetics</topic><topic>Saccharomyces cerevisiae Proteins - genetics</topic><topic>Saccharomyces cerevisiae Proteins - metabolism</topic><topic>Terbinafine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ishii, Masaki</creatorcontrib><creatorcontrib>Yamada, Tsuyoshi</creatorcontrib><creatorcontrib>Ishikawa, Kazuki</creatorcontrib><creatorcontrib>Ichinose, Koji</creatorcontrib><creatorcontrib>Monod, Michel</creatorcontrib><creatorcontrib>Ohata, Shinya</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial agents and chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ishii, Masaki</au><au>Yamada, Tsuyoshi</au><au>Ishikawa, Kazuki</au><au>Ichinose, Koji</au><au>Monod, Michel</au><au>Ohata, Shinya</au><au>Groll, Andreas H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2024-05-02</date><risdate>2024</risdate><volume>68</volume><issue>5</issue><spage>e0160923</spage><epage>e0160923</epage><pages>e0160923-e0160923</pages><issn>0066-4804</issn><eissn>1098-6596</eissn><abstract>The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment.
is the most commonly isolated fungus in dermatophytosis. In
, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast
polyamine transport kinase 2 (Ptk2), and found that
Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both
and
, Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in
. Overexpression of
Pma1 (TrPma1) in
Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine-resistant dermatophytes.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>38567956</pmid><doi>10.1128/aac.01609-23</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-1394-5455</orcidid><orcidid>https://orcid.org/0000-0003-0687-3147</orcidid><orcidid>https://orcid.org/0000-0003-4333-4433</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Antifungal Agents - pharmacology Arthrodermataceae - drug effects Arthrodermataceae - genetics Drug Resistance, Fungal - genetics Fungal Proteins - genetics Fungal Proteins - metabolism Mechanisms of Action: Physiological Effects Microbial Sensitivity Tests Mycology Phosphorylation Proton-Translocating ATPases - genetics Proton-Translocating ATPases - metabolism Saccharomyces cerevisiae - drug effects Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Terbinafine - pharmacology |
| title | The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum |
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