Pandemic Response Box® library as a source of antifungal drugs against Scedosporium and Lomentospora species

Abstract

Scedosporium and Lomentospora species are opportunistic filamentous fungi that cause localized and disseminated infections in immunocompetent and immunocompromised patients. These species are considered resistant fungi due to their low susceptibility to most current antifungal agents used in healthcare settings. The search for new compounds that could work as promising candidate antifungal drugs is an increasing field of interest. In this context, in the present study we screened the Pandemic Response Box® library (Medicines for Malaria Venture [MMV], Switzerland) to identify compounds with antifungal activity against Scedosporium and Lomentospora species. An initial screening of the drugs from this collection at 5 μM was performed using a clinical Scedosporium aurantiacum isolate according to the EUCAST protocol. Compounds with activity against this fungus were also tested against four other species (S. boydii¸ S. dehoogii, S. apiospermum and L. prolificans) at concentrations ranging from 0.078 to 10 μM. Seven compounds inhibited more than 80% of S. aurantiacum growth, three of them (alexidine, amorolfine and olorofim) were selected due to their differences in mechanism of action, especially when compared to drugs from the azole class. These compounds were more active against biofilm formation than against preformed biofilm in Scedosporium and Lomentospora species, except alexidine, which was able to decrease preformed biofilm about 50%. Analysis of the potential synergism of these compounds with voriconazole and caspofungin was performed by the checkerboard method for S. aurantiacum. The analysis by Bliss methodology revealed synergistic effects among selected drugs with caspofungin. When these drugs were combined with voriconazole, only alexidine and amorolfine showed a synergistic effect, whereas olorofim showed an antagonistic effect. Scanning electron microscopy revealed that alexidine induces morphology alterations in S. aurantiacum biofilm grown on a catheter surface. Reactive oxygen species production, mitochondrial activity and surface components were analyzed by fluorescent probes when S. aurantiacum was treated with selected drugs and revealed that some cell parameters are altered by these compounds. In conclusion, alexidine, amorolfine and olorofim were identified as promising compounds to be studied against scedosporiosis and lomentosporiosis.

Screening the medicine for malaria venture's Pandemic Response Box to identify novel inhibitors of Candida albicans and Candida auris biofilm formation

“…One such example is the Pandemic Response Box, launched in 2019 by MMV, which contains 400 diverse drug‐like molecules consisting mostly of chemotypes with in vitro activity against viral, bacterial or fungal microorganisms [18]. In the antifungal space, this collection has already been screened for molecules with activity against eumycetoma, Scedosporium and Lomentospora species, and the Mucorales [35–37]. Here we have screened the Pandemic Response Box® to identify compounds with inhibitory activity against C. albicans and C. auris biofilm formation.…”

Structural and Functional Alterations Caused by Aureobasidin A in Clinical Resistant Strains of Candida spp.

“…Scanning electron microscopy was performed according to Rollin-Pinheiro et al [35]. Candida cells were grown in supplemented RPMI in the absence (positive control) or in the presence of 0.5× MIC of aureobasidin A and incubated for 48 h at 37 • C. After the period of incubation, the cell growth was collected and processed for scanning electron microscopy.…”