A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans
ABSTRACTCandida albicans, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandin...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2024-04-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.04095-23 |
| _version_ | 1797228815062138880 |
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| author | Sara Fallah Dustin Duncan Kyle D. Reichl Michael J. Smith Wenyu Wang John A. Porco Lauren E. Brown Luke Whitesell Nicole Robbins Leah E. Cowen |
| author_facet | Sara Fallah Dustin Duncan Kyle D. Reichl Michael J. Smith Wenyu Wang John A. Porco Lauren E. Brown Luke Whitesell Nicole Robbins Leah E. Cowen |
| author_sort | Sara Fallah |
| collection | DOAJ |
| description | ABSTRACTCandida albicans, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandins. Alarmingly, the efficacy of these antifungals against C. albicans is hindered both by basal tolerance toward the drugs and the development of resistance mechanisms such as alterations of the drug’s target, modulation of stress responses, and overexpression of efflux pumps. Thus, the need to identify novel antifungal strategies is dire. To address this challenge, we screened 3,049 structurally-diverse compounds from the Boston University Center for Molecular Discovery (BU-CMD) chemical library against a C. albicans clinical isolate and identified 17 molecules that inhibited C. albicans growth by >80% relative to controls. Among the most potent compounds were CMLD013360, CMLD012661, and CMLD012693, molecules representing two distinct chemical scaffolds, including 3-hydroxyquinolinones and a xanthone natural product. Based on structural insights, CMLD013360, CMLD012661, and CMLD012693 were hypothesized to exert antifungal activity through metal chelation. Follow-up investigations revealed all three compounds exerted antifungal activity against non-albicans Candida, including Candida auris and Candida glabrata, with the xanthone natural product CMLD013360 also displaying activity against the pathogenic mould Aspergillus fumigatus. Media supplementation with metallonutrients, namely ferric or ferrous iron, rescued C. albicans growth, confirming these compounds act as metal chelators. Thus, this work identifies and characterizes two chemical scaffolds that chelate iron to inhibit the growth of the clinically relevant fungal pathogen C. albicansIMPORTANCEThe worldwide incidence of invasive fungal infections is increasing at an alarming rate. Systemic candidiasis caused by the opportunistic pathogen Candida albicans is the most common cause of life-threatening fungal infection. However, due to the limited number of antifungal drug classes available and the rise of antifungal resistance, an urgent need exists for the identification of novel treatments. By screening a compound collection from the Boston University Center for Molecular Discovery (BU-CMD), we identified three compounds representing two distinct chemical scaffolds that displayed activity against C. albicans. Follow-up analyses confirmed these molecules were also active against other pathogenic fungal species including Candida auris and Aspergillus fumigatus. Finally, we determined that these compounds inhibit the growth of C. albicans in culture through iron chelation. Overall, this observation describes two novel chemical scaffolds with antifungal activity against diverse fungal pathogens. |
| first_indexed | 2024-04-24T15:02:41Z |
| format | Article |
| id | doaj.art-0310e0d547f54976a2f68da74ed7b338 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-24T15:02:41Z |
| publishDate | 2024-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-0310e0d547f54976a2f68da74ed7b3382024-04-02T14:16:17ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972024-04-0112410.1128/spectrum.04095-23A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicansSara Fallah0Dustin Duncan1Kyle D. Reichl2Michael J. Smith3Wenyu Wang4John A. Porco5Lauren E. Brown6Luke Whitesell7Nicole Robbins8Leah E. Cowen9Department of Molecular Genetics, University of Toronto, Toronto, Ontario, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario, CanadaDepartment of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts, USADepartment of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts, USADepartment of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts, USADepartment of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts, USADepartment of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts, USADepartment of Molecular Genetics, University of Toronto, Toronto, Ontario, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario, CanadaABSTRACTCandida albicans, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandins. Alarmingly, the efficacy of these antifungals against C. albicans is hindered both by basal tolerance toward the drugs and the development of resistance mechanisms such as alterations of the drug’s target, modulation of stress responses, and overexpression of efflux pumps. Thus, the need to identify novel antifungal strategies is dire. To address this challenge, we screened 3,049 structurally-diverse compounds from the Boston University Center for Molecular Discovery (BU-CMD) chemical library against a C. albicans clinical isolate and identified 17 molecules that inhibited C. albicans growth by >80% relative to controls. Among the most potent compounds were CMLD013360, CMLD012661, and CMLD012693, molecules representing two distinct chemical scaffolds, including 3-hydroxyquinolinones and a xanthone natural product. Based on structural insights, CMLD013360, CMLD012661, and CMLD012693 were hypothesized to exert antifungal activity through metal chelation. Follow-up investigations revealed all three compounds exerted antifungal activity against non-albicans Candida, including Candida auris and Candida glabrata, with the xanthone natural product CMLD013360 also displaying activity against the pathogenic mould Aspergillus fumigatus. Media supplementation with metallonutrients, namely ferric or ferrous iron, rescued C. albicans growth, confirming these compounds act as metal chelators. Thus, this work identifies and characterizes two chemical scaffolds that chelate iron to inhibit the growth of the clinically relevant fungal pathogen C. albicansIMPORTANCEThe worldwide incidence of invasive fungal infections is increasing at an alarming rate. Systemic candidiasis caused by the opportunistic pathogen Candida albicans is the most common cause of life-threatening fungal infection. However, due to the limited number of antifungal drug classes available and the rise of antifungal resistance, an urgent need exists for the identification of novel treatments. By screening a compound collection from the Boston University Center for Molecular Discovery (BU-CMD), we identified three compounds representing two distinct chemical scaffolds that displayed activity against C. albicans. Follow-up analyses confirmed these molecules were also active against other pathogenic fungal species including Candida auris and Aspergillus fumigatus. Finally, we determined that these compounds inhibit the growth of C. albicans in culture through iron chelation. Overall, this observation describes two novel chemical scaffolds with antifungal activity against diverse fungal pathogens.https://journals.asm.org/doi/10.1128/spectrum.04095-23metal chelatorfungal pathogenCandidaAspergillusironchemical library |
| spellingShingle | Sara Fallah Dustin Duncan Kyle D. Reichl Michael J. Smith Wenyu Wang John A. Porco Lauren E. Brown Luke Whitesell Nicole Robbins Leah E. Cowen A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans Microbiology Spectrum metal chelator fungal pathogen Candida Aspergillus iron chemical library |
| title | A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans |
| title_full | A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans |
| title_fullStr | A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans |
| title_full_unstemmed | A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans |
| title_short | A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans |
| title_sort | chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen candida albicans |
| topic | metal chelator fungal pathogen Candida Aspergillus iron chemical library |
| url | https://journals.asm.org/doi/10.1128/spectrum.04095-23 |
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