TY - JOUR
T1 - Screening of the Pandemic Response Box Reveals an Association between Antifungal Effects of MMV1593537 and the Cell Wall of Cryptococcus neoformans, Cryptococcus deuterogattii, and Candida auris
AU - de Oliveira, Haroldo C.
AU - Castelli, Rafael F.
AU - Reis, Flavia C.G.
AU - Samby, Kirandeep
AU - Nosanchuk, Joshua D.
AU - Alves, Lysangela R.
AU - Rodrigues, Marcio L.
N1 - Funding Information:
We thank the Medicines for Malaria Venture for providing the Pandemic Response Box. M.L.R. is supported by grants from the Brazilian Ministry of Health (grant 440015/ 2018-9), Conselho Nacional de Desenvolvimento Científico e Tecnológico (grants 405520/2018-2 and 301304/2017-3), and Fiocruz (grants PROEP-ICC 442186/2019-3, VPPCB-007-FIO-18, and VPPIS-001-FIO18). M.L.R. also acknowledges support from the Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas. H.C.dO. received scholarships from the Inova Program of Fiocruz. F.C.G.R. received a scholarship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazil, Finance Code 001). J.D.N. is supported in part by NIH R21AI156104. The funders had no role in the decision to publish, or preparation of the manuscript. We are grateful to the Program for Technological Development in Tools for Health (RPT-FIOCRUZ) for use of the microscopy facility (RPT07C, Carlos Chagas Institute, Fiocruz, Paraná). M.L.R. is currently on leave from the position of associate professor at the Microbiology Institute of the Federal University of Rio de Janeiro, Brazil. We have no conflicts of interest to report.
Funding Information:
We thank the Medicines for Malaria Venture for providing the Pandemic Response Box. M.L.R. is supported by grants from the Brazilian Ministry of Health (grant 440015/ 2018-9), Conselho Nacional de Desenvolvimento Científico e Tecnológico (grants 405520/2018-2 and 301304/2017-3), and Fiocruz (grants PROEP-ICC 442186/2019-3, VPPCB-007-FIO-18, and VPPIS-001-FIO18). M.L.R. also acknowledges support from the Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas. H.C.dO. received scholarships from the Inova Program of Fiocruz. F.C.G.R. received a scholarship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazil, Finance Code 001). J.D.N. is supported in part by NIH R21AI156104.
Publisher Copyright:
Copyright © 2022 de Oliveira et al.
PY - 2022/6
Y1 - 2022/6
N2 - There is an urgent unmet need for novel antifungals. In this study, we searched for novel antifungal activities in the Pandemic Response Box, a collection of 400 structurally diverse compounds in various phases of drug discovery. We identified five molecules which could control the growth of Cryptococcus neoformans, Cryptococcus deuterogattii, and the emerging global threat Candida auris. After eliminating compounds which demonstrated paradoxical antifungal effects or toxicity to mammalian macrophages, we selected compound MMV1593537 as a nontoxic, fungicidal molecule for further characterization of antifungal activity. Scanning electron microscopy revealed that MMV1593537 affected cellular division in all three pathogens. In Cryptococcus, MMV1593537 caused a reduction in capsular dimensions. Treatment with MMV1593537 resulted in increased detection of cell wall chitooligomers in these three species. Since chitooligomers are products of the enzymatic hydrolysis of chitin, we investigated whether surface chitinase activity was altered in response to MMV1593537 exposure. We observed peaks of enzyme activity in C. neoformans and C. deuterogattii in response to MMV1593537. We did not detect any surface chitinase activity in C. auris. Our results suggest that MMV1593537 is a promising, nontoxic fungicide whose mechanism of action, at least in Cryptococcus spp, requires chitinase-mediated hydrolysis of chitin. IMPORTANCE The development of novel antifungals is a matter of urgency. In this study, we evaluated antifungal activities in a collection of 400 molecules, using highly lethal fungal pathogens as targets. One of these molecules, namely, MMV1593537, was not toxic to host cells and controlled the growth of isolates of Cryptococcus neoformans, C. deuterogattii, C. gattii, Candida auris, C. albicans, C. parapsilosis, and C. krusei. We tested the mechanisms of antifungal action of MMV1593537 in the Cryptococcus and C. auris models and concluded that the compound affects the cell wall, a structure which is essential for fungal life. At least in Cryptococcus, this effect involved chitinase, an enzyme which is required for remodeling the cell wall. Our results suggest that MMV1593537 is a candidate for future antifungal development.
AB - There is an urgent unmet need for novel antifungals. In this study, we searched for novel antifungal activities in the Pandemic Response Box, a collection of 400 structurally diverse compounds in various phases of drug discovery. We identified five molecules which could control the growth of Cryptococcus neoformans, Cryptococcus deuterogattii, and the emerging global threat Candida auris. After eliminating compounds which demonstrated paradoxical antifungal effects or toxicity to mammalian macrophages, we selected compound MMV1593537 as a nontoxic, fungicidal molecule for further characterization of antifungal activity. Scanning electron microscopy revealed that MMV1593537 affected cellular division in all three pathogens. In Cryptococcus, MMV1593537 caused a reduction in capsular dimensions. Treatment with MMV1593537 resulted in increased detection of cell wall chitooligomers in these three species. Since chitooligomers are products of the enzymatic hydrolysis of chitin, we investigated whether surface chitinase activity was altered in response to MMV1593537 exposure. We observed peaks of enzyme activity in C. neoformans and C. deuterogattii in response to MMV1593537. We did not detect any surface chitinase activity in C. auris. Our results suggest that MMV1593537 is a promising, nontoxic fungicide whose mechanism of action, at least in Cryptococcus spp, requires chitinase-mediated hydrolysis of chitin. IMPORTANCE The development of novel antifungals is a matter of urgency. In this study, we evaluated antifungal activities in a collection of 400 molecules, using highly lethal fungal pathogens as targets. One of these molecules, namely, MMV1593537, was not toxic to host cells and controlled the growth of isolates of Cryptococcus neoformans, C. deuterogattii, C. gattii, Candida auris, C. albicans, C. parapsilosis, and C. krusei. We tested the mechanisms of antifungal action of MMV1593537 in the Cryptococcus and C. auris models and concluded that the compound affects the cell wall, a structure which is essential for fungal life. At least in Cryptococcus, this effect involved chitinase, an enzyme which is required for remodeling the cell wall. Our results suggest that MMV1593537 is a candidate for future antifungal development.
KW - Candida auris
KW - Cryptococcus
KW - antifungals
KW - drug screening
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U2 - 10.1128/spectrum.00601-22
DO - 10.1128/spectrum.00601-22
M3 - Article
C2 - 35471056
AN - SCOPUS:85133214908
VL - 10
JO - Microbiology spectrum
JF - Microbiology spectrum
SN - 2165-0497
IS - 3
ER -