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Transcriptome Profile of the Response of Paracoccidioides spp. to a Camphene Thiosemicarbazide Derivative
Lívia do Carmo Silva1, Diana Patrícia Tamayo Ossa2, Symone Vitoriano da Conceição Castro1
1Laboratório de Biologia Molecular, Instituto de Patologia Tropical e Saúde Pública Universidade Federal de Goiás, Goiânia, Brazil.
Abstract:
Paracoccidioidomycosis (PCM) is a systemic granulomatous human mycosis caused by fungi of the genus Paracoccidioides, which is geographically restricted to Latin America. Inhalation of spores, the infectious particles of the fungus, is a common route of infection. The PCM treatment of choice is azoles such as itraconazole, but sulfonamides and amphotericin B are used in some cases despite their toxicity to mammalian cells. The current availability of treatments highlights the need to identify and characterize novel targets for antifungal treatment of PCM as well as the need to search for new antifungal compounds obtained from natural sources or by chemical synthesis. To this end, we evaluated the antifungal activity of a camphene thiosemicarbazide derivative (TSC-C) compound on Paracoccidioides yeast. To determine the response of Paracoccidioides spp. to TSC-C, we analyzed the transcriptional profile of the fungus after 8 h of contact with the compound. The results demonstrate that Paracoccidioides lutzii induced the expression of genes related to metabolism; cell cycle and DNA processing; biogenesis of cellular components; cell transduction/signal; cell rescue, defense and virulence; cellular transport, transport facilities and transport routes; energy; protein synthesis; protein fate; transcription; and other proteins without classification. Additionally, we observed intensely inhibited genes related to protein synthesis. Analysis by fluorescence microscopy and flow cytometry revealed that the compound induced the production of reactive oxygen species. Using an isolate with down-regulated SOD1 gene expression (SOD1-aRNA), we sought to determine the function of this gene in the defense of Paracoccidioides yeast cells against the compound. Mutant cells were more susceptible to TSC-C, demonstrating the importance of this gene in response to the compound. The results presented herein suggest that TSC-C is a promising candidate for PCM treatment.
Insights
A novel camphene thiosemicarbazide derivative (TSC-C) shows promise for treating Paracoccidioidomycosis (PCM). This compound effectively targets Paracoccidioides yeast by inducing reactive oxygen species and highlighting the role of SOD1 in fungal defense.
Area of Science:
- Mycology
- Infectious Diseases
- Medicinal Chemistry
Background:
- Paracoccidioidomycosis (PCM) is a Latin American fungal infection treated with azoles, sulfonamides, or amphotericin B.
- Existing treatments have limitations, necessitating the search for novel antifungal compounds and therapeutic targets.
- Inhalation of Paracoccidioides spores is the primary infection route.
Purpose of the Study:
- To evaluate the antifungal activity of a camphene thiosemicarbazide derivative (TSC-C) against Paracoccidioides yeast.
- To elucidate the molecular mechanisms underlying the antifungal action of TSC-C.
- To assess the potential of TSC-C as a new therapeutic agent for PCM.
Main Methods:
- Transcriptional profiling of Paracoccidioides lutzii after exposure to TSC-C.
- Fluorescence microscopy and flow cytometry to detect reactive oxygen species (ROS) production.
- Antifungal susceptibility testing using a SOD1-down-regulated Paracoccidioides isolate (SOD1-aRNA).
Main Results:
- TSC-C modulated the expression of numerous genes involved in fungal metabolism, cell cycle, signal transduction, and virulence.
- A significant inhibition of protein synthesis-related genes was observed.
- TSC-C induced the production of reactive oxygen species in Paracoccidioides yeast.
- The SOD1 gene is crucial for fungal defense against TSC-C, as evidenced by increased susceptibility in the SOD1-aRNA mutant.
Conclusions:
- The camphene thiosemicarbazide derivative (TSC-C) exhibits significant antifungal activity against Paracoccidioides yeast.
- TSC-C's mechanism involves ROS generation and impacts various cellular processes, including protein synthesis.
- The SOD1 gene plays a vital role in the yeast's resistance to TSC-C, suggesting it as a potential target.
- TSC-C represents a promising candidate for the development of novel PCM treatments.
