Trans-chalcone activity against Trichophyton rubrum relies on an interplay between signaling pathways related to cell wall integrity and fatty acid metabolism

Author(s):Show less -

Bitencourt, Tamires Aparecida ^{[1, 2]} ; Macedo, Claudia ^[1] ; Franco, Matheus Eloy ^{[2, 3]} ; Rocha, Marina Campos ^[4] ; Moreli, Igor Sawasaki ^[2] ; Micheloto Cantelli, Bruna Aline ^[2] ; Sanches, Pablo Rodrigo ^[1] ; Beleboni, Rene Oliveira ^[2] ; Malavazi, Iran ^[4] ; Passos, Geraldo Aleixo ^[1] ; Marins, Mozart ^[2] ; Fachin, Ana Lucia ^[2]

Affiliation

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Genet, Ribeirao Preto, SP - Brazil

^[2] Univ Ribeirao Preto, Unidade Biotecnol, Ave Costabile Romano 2201, BR-14096900 Ribeirao Preto, SP - Brazil

^[3] Inst Fed Sul Minas Campus Machado, Machado - Brazil

^[4] Univ Fed Sao Carlos, Dept Genet & Evolucao, CCBS, Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: BMC Genomics; v. 20, MAY 22 2019.
• Web of Science Citations: 1

Abstract

BackgroundTrichophyton rubrum is the main etiological agent of skin and nail infections worldwide. Because of its keratinolytic activity and anthropophilic nature, infection models based on the addition of protein substrates have been employed to assess transcriptional profiles and to elucidate aspects related to host-pathogen interactions. Chalcones are widespread compounds with pronounced activity against dermatophytes. The toxicity of trans-chalcone towards T. rubrum is not fully understood but seems to rely on diverse cellular targets. Within this context, a better understanding of the mode of action of trans-chalcone may help identify new strategies of antifungal therapy and reveal new chemotherapeutic targets. This work aimed to assess the transcriptional profile of T. rubrum grown on different protein sources (keratin or elastin) to mimic natural infection sites and exposed to trans-chalcone in order to elucidate the mechanisms underlying the antifungal activity of trans-chalcone.ResultsOverall, the use of different protein sources caused only slight differences in the transcriptional profile of T. rubrum. The main differences were the modulation of proteases and lipases in gene categories when T. rubrum was grown on keratin and elastin, respectively. In addition, some genes encoding heat shock proteins were up-regulated during the growth of T. rubrum on keratin. The transcriptional profile of T. rubrum exposed to trans-chalcone included four main categories: fatty acid and lipid metabolism, overall stress response, cell wall integrity pathway, and alternative energy metabolism. Consistently, T. rubrum Mapk was strongly activated during the first hours of trans-chalcone exposure. Noteworthy, trans-chalcone inhibited genes involved in keratin degradation. The results also showed effects of trans-chalcone on fatty acid synthesis and metabolic pathways involved in acetyl-CoA supply.ConclusionOur results suggest that the mode of action of trans-chalcone is related to pronounced changes in fungal metabolism, including an imbalance between fatty acid synthesis and degradation that interferes with cell membrane and cell wall integrity. In addition, this compound exerts activity against important virulence factors. Taken together, trans-chalcone acts on targets related to dermatophyte physiology and the infection process. (AU)

• FAPESP's process: 16/22701-9 - Study of the response to antifungal and fungal-host interaction of T.rubrum dermatophyte using different models of infection
• Grantee: Ana Lucia Fachin Saltoratto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/02920-7 - Transcriptome of the dermatophyte Trichophyton rubrum in response to antifungal transchalcona in culture conditions that simulate infection
• Grantee: Tamires Aparecida Bitencourt
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/23435-8 - Molecular mechanisms involved in resistance and adaptive response to fungal inhibitors
• Grantee: Tamires Aparecida Bitencourt
• Support Opportunities: Scholarships in Brazil - Post-Doctoral