Banca de QUALIFICAÇÃO: THALITA KELLEN SILVA PINHEIRO

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : THALITA KELLEN SILVA PINHEIRO
DATE: 01/12/2025
TIME: 14:00
LOCAL: Plataforma TEAMS
TITLE:

HSP90 inhibitors and antimicrobial peptides as strategies against multidrug-resistant and neglected fungi.

KEY WORDS:

HSP90; HSP90 inhibitors; antimicrobial peptides; antifungal resistance; synergism; Candida auris; invasive mycoses; pathogenic fungus; WHO fungal priority list; neglected fungi

PAGES: 43
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUMMARY:

Fungal infections represent a public health challenge due to high mortality rates and healthcare costs. The limited therapeutic arsenal, coupled with the adverse effects/toxicity of conventional drugs highlights the need for new strategies with distinct mechanisms of action. The molecular chaperone HSP90 is a promising target due to its essential role in regulating stress responses, virulence, and antifungal resistance. Simultaneously, antimicrobial peptides have attracted attention for their versatility and multiple mechanisms of action. In this work, we evaluated HSP90 inhibitors and antimicrobial peptides (AMPs) as alternatives against globally relevant pathogenic fungi. Sixty-six HSP90 inhibitors compounds were screened against WHO priority species, and two antimicrobial peptides (ToAP1 and ToAP2) against C. auris and C. duobushaemulonii, using the broth microdilution method (CLSI). Six HSP90 inhibitors exhibited activity against P. brasiliensis (MIC range 6.25 to 25 µM), and one compound showed a broad spectrum (MIC range 12.5 to 50 µM), active even against multidrug-resistant species such as C. auris and C. duobushaemulonii. Morphological alterations were observed in C. albicans treated with the compounds, suggesting that HSP90 inhibition interferes with pathways associated with morphogenesis. Checkerboard assays revealed additive effects between HSP90 inhibitors and amphotericin B or micafungin, broadening the antifungal efficacy of the compounds. Among the peptides tested, only ToAP2 showed activity (MIC 25-50 µM) against C. duobushaemuloni and C. auris, affecting morphology. ToAP2 exhibited synergy with amphotericin B (fractional concentration indices 0.25 to 0.49) and caspofungin (0.03 to 0.31), with no evidence of antagonism in the combinations tested. Furthermore, amphotericin B demonstrated significant activity against mature biofilms. Taken together, the results highlight HSP90 as a promising therapeutic target and ToAP2 as a potential adjuvant in combination therapies. The combination of HSP90 inhibitors and peptides with conventional antifungals enhances efficacy against resistant species and clinically relevant species, broadening the spectrum of action. HSP90 inhibitors and the PAM ToAP2 can be used as templates for the rational design of more potent analogs.

COMMITTEE MEMBERS:
Externo ao Programa - 2346559 - HUGO COSTA PAES - UnBExterno ao Programa - 2243078 - LUIZ ANTONIO SOARES ROMEIRO - nullPresidente - ***.356.791-** - MARIA SUELI SOARES FELIPE - USP
Externo à Instituição - Michel Lopes Leite - UCB