Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformans
Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningitis in >152,000 immunocompromised individuals annually, leading to 112,000 yearly deaths. The four classes of existing antifungal agents target plasma membrane sterols (ergosterol), nucleic acid synthesis, and cell...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1339303/full |
| _version_ | 1797353965892927488 |
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| author | Brittney N. Conn Jacob A. Lieberman Priscilla Chatman Kaitlyn Cotton Martha A. Essandoh Mohammad Ebqa’ai Toby L. Nelson Karen L. Wozniak |
| author_facet | Brittney N. Conn Jacob A. Lieberman Priscilla Chatman Kaitlyn Cotton Martha A. Essandoh Mohammad Ebqa’ai Toby L. Nelson Karen L. Wozniak |
| author_sort | Brittney N. Conn |
| collection | DOAJ |
| description | Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningitis in >152,000 immunocompromised individuals annually, leading to 112,000 yearly deaths. The four classes of existing antifungal agents target plasma membrane sterols (ergosterol), nucleic acid synthesis, and cell wall synthesis. Existing drugs are not highly effective against Cryptococcus, and antifungal drug resistance is an increasing problem. A novel antimicrobial compound, a eumelanin-inspired indoylenepheyleneethynylene, EIPE-1, was synthesized and has antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MSRA), but not towards Gram-negative organisms. Based on EIPE-1’s antibacterial activity, we hypothesized that EIPE-1 could have antifungal activity. For these studies, we tested EIPE-1 against C. neoformans strain H99 and 6 additional cryptococcal clinical isolates. We examined antifungal activity, cytotoxicity, effects on fungal gene expression, and mechanism of action of EIPE-1. Results showed that EIPE-1 has fungicidal effects on seven cryptococcal strains with MICs ranging from 1.56 to 3.125 μg/mL depending on the strain, and it is non-toxic to mammalian cells. We conducted scanning and transmission electron microscopy on the exposed cells to examine structural changes to the organism following EIPE-1 treatment. Cells exposed displayed structural changes to their cell wall and membranes, with internal contents leaking out of the cells. To understand the effect of EIPE-1 on fungal gene expression, RNA sequencing was conducted. Results showed that EIPE-1 affects several processes involved stress response, ergosterol biosynthesis, capsule biosynthesis, and cell wall attachment and remodeling. Therefore, our studies demonstrate that EIPE-1 has antifungal activity against C. neoformans, which affects both cellular structure and gene expression of multiple fungal pathways involved in cell membrane stability and viability. |
| first_indexed | 2024-03-08T13:38:33Z |
| format | Article |
| id | doaj.art-b32549c8a7a248ec890c395ad79b564f |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-03-08T13:38:33Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-b32549c8a7a248ec890c395ad79b564f2024-01-16T13:45:06ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2024-01-011410.3389/fmicb.2023.13393031339303Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformansBrittney N. Conn0Jacob A. Lieberman1Priscilla Chatman2Kaitlyn Cotton3Martha A. Essandoh4Mohammad Ebqa’ai5Toby L. Nelson6Karen L. Wozniak7Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United StatesDepartment of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United StatesDepartment of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United StatesDepartment of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United StatesDepartment of Chemistry, Oklahoma State University, Stillwater, OK, United StatesDepartment of Chemistry, Oklahoma State University, Stillwater, OK, United StatesDepartment of Chemistry, Oklahoma State University, Stillwater, OK, United StatesDepartment of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United StatesCryptococcus neoformans is an opportunistic fungal pathogen that causes meningitis in >152,000 immunocompromised individuals annually, leading to 112,000 yearly deaths. The four classes of existing antifungal agents target plasma membrane sterols (ergosterol), nucleic acid synthesis, and cell wall synthesis. Existing drugs are not highly effective against Cryptococcus, and antifungal drug resistance is an increasing problem. A novel antimicrobial compound, a eumelanin-inspired indoylenepheyleneethynylene, EIPE-1, was synthesized and has antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MSRA), but not towards Gram-negative organisms. Based on EIPE-1’s antibacterial activity, we hypothesized that EIPE-1 could have antifungal activity. For these studies, we tested EIPE-1 against C. neoformans strain H99 and 6 additional cryptococcal clinical isolates. We examined antifungal activity, cytotoxicity, effects on fungal gene expression, and mechanism of action of EIPE-1. Results showed that EIPE-1 has fungicidal effects on seven cryptococcal strains with MICs ranging from 1.56 to 3.125 μg/mL depending on the strain, and it is non-toxic to mammalian cells. We conducted scanning and transmission electron microscopy on the exposed cells to examine structural changes to the organism following EIPE-1 treatment. Cells exposed displayed structural changes to their cell wall and membranes, with internal contents leaking out of the cells. To understand the effect of EIPE-1 on fungal gene expression, RNA sequencing was conducted. Results showed that EIPE-1 affects several processes involved stress response, ergosterol biosynthesis, capsule biosynthesis, and cell wall attachment and remodeling. Therefore, our studies demonstrate that EIPE-1 has antifungal activity against C. neoformans, which affects both cellular structure and gene expression of multiple fungal pathways involved in cell membrane stability and viability.https://www.frontiersin.org/articles/10.3389/fmicb.2023.1339303/fullCryptococcus neoformansantifungalnovel antifungal compoundEIPE-1eumelanin |
| spellingShingle | Brittney N. Conn Jacob A. Lieberman Priscilla Chatman Kaitlyn Cotton Martha A. Essandoh Mohammad Ebqa’ai Toby L. Nelson Karen L. Wozniak Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformans Frontiers in Microbiology Cryptococcus neoformans antifungal novel antifungal compound EIPE-1 eumelanin |
| title | Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformans |
| title_full | Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformans |
| title_fullStr | Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformans |
| title_full_unstemmed | Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformans |
| title_short | Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformans |
| title_sort | antifungal activity of eumelanin inspired indoylenepheyleneethynylene against cryptococcus neoformans |
| topic | Cryptococcus neoformans antifungal novel antifungal compound EIPE-1 eumelanin |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1339303/full |
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