Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of <i>Candida albicans</i>
The incidence of infections caused by <i>Candida</i> species, specifically by drug-resistant isolates, is a major health concern as they can disseminate to and colonize most vital organs, enhancing morbidity and mortality. Several molecular mechanisms have been reported to be involved in...
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MDPI AG
2024-03-01
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| Series: | Journal of Fungi |
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| author | Bhabasha Gyanadeep Utkalaja Satya Ranjan Sahu Sushree Subhashree Parida Narottam Acharya |
| author_facet | Bhabasha Gyanadeep Utkalaja Satya Ranjan Sahu Sushree Subhashree Parida Narottam Acharya |
| author_sort | Bhabasha Gyanadeep Utkalaja |
| collection | DOAJ |
| description | The incidence of infections caused by <i>Candida</i> species, specifically by drug-resistant isolates, is a major health concern as they can disseminate to and colonize most vital organs, enhancing morbidity and mortality. Several molecular mechanisms have been reported to be involved in drug resistance. These are mostly drug- and isolate-specific. Here, we characterized three different genetically modified strains of <i>C. albicans</i> that were multi-drug-resistant (MDR) and deciphered a uniform mechanism responsible for resistance. DNA polymerase epsilon (Polε) is a leading strand-specific polymerase consisting of four subunits, namely, Pol2, Dpb2, Dpb3, and Dpb4. The deletion of one or both of the Dpb3 and Dpb4 subunits in <i>C. albicans</i> rendered multi-drug resistance. A detailed characterization of these strains revealed that acquired mutagenesis, drug efflux pumps, and other known mechanisms did not play a significant role because the complemented strain showed drug sensitivity. More importantly, the function of heat shock protein 90 (Hsp90) in these knockout strains is critical for reducing susceptibility to several antifungal drugs. Cell wall deformity and composition in these strains can add to such a phenotype. The inhibition of Hsp90 function by geldanamycin and tricostatin A sensitized the MDR strains to antifungals. Considering our earlier research and this report, we suggest that replication stress induces Hsp90 expression and activity in order to orchestrate a cellular stress response circuit and thus develop fungal drug resistance. Thus, Hsp90 is an important drug target for use in combinatorial therapy. |
| first_indexed | 2024-04-24T18:07:35Z |
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| issn | 2309-608X |
| language | English |
| last_indexed | 2024-04-24T18:07:35Z |
| publishDate | 2024-03-01 |
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| series | Journal of Fungi |
| spelling | doaj.art-f3403095b96443f3a6d63c619d0b6e4e2024-03-27T13:49:44ZengMDPI AGJournal of Fungi2309-608X2024-03-0110322210.3390/jof10030222Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of <i>Candida albicans</i>Bhabasha Gyanadeep Utkalaja0Satya Ranjan Sahu1Sushree Subhashree Parida2Narottam Acharya3Laboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar 751023, IndiaLaboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar 751023, IndiaLaboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar 751023, IndiaLaboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar 751023, IndiaThe incidence of infections caused by <i>Candida</i> species, specifically by drug-resistant isolates, is a major health concern as they can disseminate to and colonize most vital organs, enhancing morbidity and mortality. Several molecular mechanisms have been reported to be involved in drug resistance. These are mostly drug- and isolate-specific. Here, we characterized three different genetically modified strains of <i>C. albicans</i> that were multi-drug-resistant (MDR) and deciphered a uniform mechanism responsible for resistance. DNA polymerase epsilon (Polε) is a leading strand-specific polymerase consisting of four subunits, namely, Pol2, Dpb2, Dpb3, and Dpb4. The deletion of one or both of the Dpb3 and Dpb4 subunits in <i>C. albicans</i> rendered multi-drug resistance. A detailed characterization of these strains revealed that acquired mutagenesis, drug efflux pumps, and other known mechanisms did not play a significant role because the complemented strain showed drug sensitivity. More importantly, the function of heat shock protein 90 (Hsp90) in these knockout strains is critical for reducing susceptibility to several antifungal drugs. Cell wall deformity and composition in these strains can add to such a phenotype. The inhibition of Hsp90 function by geldanamycin and tricostatin A sensitized the MDR strains to antifungals. Considering our earlier research and this report, we suggest that replication stress induces Hsp90 expression and activity in order to orchestrate a cellular stress response circuit and thus develop fungal drug resistance. Thus, Hsp90 is an important drug target for use in combinatorial therapy.https://www.mdpi.com/2309-608X/10/3/222DNA replicationDNA polymerase epsilon<i>Candida</i>candidiasisHsp90azoles |
| spellingShingle | Bhabasha Gyanadeep Utkalaja Satya Ranjan Sahu Sushree Subhashree Parida Narottam Acharya Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of <i>Candida albicans</i> Journal of Fungi DNA replication DNA polymerase epsilon <i>Candida</i> candidiasis Hsp90 azoles |
| title | Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of <i>Candida albicans</i> |
| title_full | Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of <i>Candida albicans</i> |
| title_fullStr | Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of <i>Candida albicans</i> |
| title_full_unstemmed | Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of <i>Candida albicans</i> |
| title_short | Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of <i>Candida albicans</i> |
| title_sort | hsp90 mediated multi drug resistance in dna polymerase defective strains of i candida albicans i |
| topic | DNA replication DNA polymerase epsilon <i>Candida</i> candidiasis Hsp90 azoles |
| url | https://www.mdpi.com/2309-608X/10/3/222 |
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