Discovery of a Novel Antifungal Agent in the Pathogen Box
ABSTRACT Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Cryptococcus neoformans and Candida albicans are two of the most common fungal pathogens of humans, together accounting for a staggering 1.4 million infections annually, with ve...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2017-04-01
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| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSphere.00120-17 |
| _version_ | 1818836613552144384 |
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| author | François L. Mayer James W. Kronstad |
| author_facet | François L. Mayer James W. Kronstad |
| author_sort | François L. Mayer |
| collection | DOAJ |
| description | ABSTRACT Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Cryptococcus neoformans and Candida albicans are two of the most common fungal pathogens of humans, together accounting for a staggering 1.4 million infections annually, with very high mortality rates. Patients with dysfunctional immune systems, such as individuals with HIV/AIDS, are particularly susceptible to fungal infections. Unfortunately, relatively few antifungal drugs are currently available and fungi frequently develop resistance, further complicating treatment approaches. In this study, we screened the Pathogen Box chemical library (Medicines for Malaria Venture, Switzerland) in an effort to identify novel antifungal compounds. This approach led to the discovery of a novel, highly potent antifungal agent with activity against both C. neoformans and C. albicans. Our initial study of the mechanism of action suggested that this novel compound prevents fungal proliferation by targeting the ability of C. neoformans to withstand stress at the plasma membrane and cell wall. Because this compound had previously been shown to have low toxicity for mammalian cells, we propose that it represents an attractive lead compound for further antifungal drug development. IMPORTANCE Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions. |
| first_indexed | 2024-12-19T03:09:24Z |
| format | Article |
| id | doaj.art-217d8ba7035a4a5caea4d88acd988b93 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-12-19T03:09:24Z |
| publishDate | 2017-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-217d8ba7035a4a5caea4d88acd988b932022-12-21T20:38:03ZengAmerican Society for MicrobiologymSphere2379-50422017-04-012210.1128/mSphere.00120-17Discovery of a Novel Antifungal Agent in the Pathogen BoxFrançois L. Mayer0James W. Kronstad1Michael Smith Laboratories, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, CanadaMichael Smith Laboratories, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, CanadaABSTRACT Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Cryptococcus neoformans and Candida albicans are two of the most common fungal pathogens of humans, together accounting for a staggering 1.4 million infections annually, with very high mortality rates. Patients with dysfunctional immune systems, such as individuals with HIV/AIDS, are particularly susceptible to fungal infections. Unfortunately, relatively few antifungal drugs are currently available and fungi frequently develop resistance, further complicating treatment approaches. In this study, we screened the Pathogen Box chemical library (Medicines for Malaria Venture, Switzerland) in an effort to identify novel antifungal compounds. This approach led to the discovery of a novel, highly potent antifungal agent with activity against both C. neoformans and C. albicans. Our initial study of the mechanism of action suggested that this novel compound prevents fungal proliferation by targeting the ability of C. neoformans to withstand stress at the plasma membrane and cell wall. Because this compound had previously been shown to have low toxicity for mammalian cells, we propose that it represents an attractive lead compound for further antifungal drug development. IMPORTANCE Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions.https://journals.asm.org/doi/10.1128/mSphere.00120-17antifungal drugCandida albicansCryptococcus gattiiCryptococcus neoformansPathogen Box |
| spellingShingle | François L. Mayer James W. Kronstad Discovery of a Novel Antifungal Agent in the Pathogen Box mSphere antifungal drug Candida albicans Cryptococcus gattii Cryptococcus neoformans Pathogen Box |
| title | Discovery of a Novel Antifungal Agent in the Pathogen Box |
| title_full | Discovery of a Novel Antifungal Agent in the Pathogen Box |
| title_fullStr | Discovery of a Novel Antifungal Agent in the Pathogen Box |
| title_full_unstemmed | Discovery of a Novel Antifungal Agent in the Pathogen Box |
| title_short | Discovery of a Novel Antifungal Agent in the Pathogen Box |
| title_sort | discovery of a novel antifungal agent in the pathogen box |
| topic | antifungal drug Candida albicans Cryptococcus gattii Cryptococcus neoformans Pathogen Box |
| url | https://journals.asm.org/doi/10.1128/mSphere.00120-17 |
| work_keys_str_mv | AT francoislmayer discoveryofanovelantifungalagentinthepathogenbox AT jameswkronstad discoveryofanovelantifungalagentinthepathogenbox |