TY - JOUR
T1 - Inhibitors of DNA topoisomerases i and II applied to Candida dubliniensis reduce growth, viability, the generation of petite mutants and toxicity, while acting synergistically with fluconazole
AU - Tagle-Olmedo, Tania
AU - Andrade-Pavón, Dulce
AU - Martínez-Gamboa, Areli
AU - Gómez-García, Omar
AU - García-Sierra, Francisco
AU - Hernández-Rodríguez, César
AU - Villa-Tanaca, Lourdes
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of FEMS.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - The increasing resistance of Candida species to azoles emphasizes the urgent need for new antifungal agents with novel mechanisms of action. The aim of this study was to examine the effect of three DNA topoisomerase inhibitors of plant origin (camptothecin, etoposide and curcumin) on the growth of Candida dubliniensis. The phylogenetic analysis showed a close relationship between the topoisomerase enzymes of C. dubliniensis and Candida albicans. The alignment of the amino acid sequences of topoisomerase I and II of yeasts and humans evidenced conserved domains. The docking study revealed affinity of the test compounds for the active site of topoisomerase I and II in C. dubliniensis. Curcumin and camptothecin demonstrated a stronger in vitro antifungal effect than the reference drugs (fluconazole and itraconazole). Significant synergistic activity between the topoisomerase inhibitors and fluconazole at the highest concentration (750 μM) was observed. Fluconazole induced the petite phenotype to a greater degree than the topoisomerase inhibitors, indicating a tendency to generate resistance. Lower toxicity was found for such inhibitors versus reference drugs on Galleria mellonella larva. The topoisomerase inhibitors exhibited promising antifungal activity, and the DNA topoisomerase enzymes of C. dubliniensis proved to be an excellent model for evaluating new antifungal compounds.
AB - The increasing resistance of Candida species to azoles emphasizes the urgent need for new antifungal agents with novel mechanisms of action. The aim of this study was to examine the effect of three DNA topoisomerase inhibitors of plant origin (camptothecin, etoposide and curcumin) on the growth of Candida dubliniensis. The phylogenetic analysis showed a close relationship between the topoisomerase enzymes of C. dubliniensis and Candida albicans. The alignment of the amino acid sequences of topoisomerase I and II of yeasts and humans evidenced conserved domains. The docking study revealed affinity of the test compounds for the active site of topoisomerase I and II in C. dubliniensis. Curcumin and camptothecin demonstrated a stronger in vitro antifungal effect than the reference drugs (fluconazole and itraconazole). Significant synergistic activity between the topoisomerase inhibitors and fluconazole at the highest concentration (750 μM) was observed. Fluconazole induced the petite phenotype to a greater degree than the topoisomerase inhibitors, indicating a tendency to generate resistance. Lower toxicity was found for such inhibitors versus reference drugs on Galleria mellonella larva. The topoisomerase inhibitors exhibited promising antifungal activity, and the DNA topoisomerase enzymes of C. dubliniensis proved to be an excellent model for evaluating new antifungal compounds.
KW - Candida dubliniensis
KW - DNA topoisomerase I (EC 5.99.1.2)
KW - DNA topoisomerase II (EC 5.99.1.3)
KW - Topo I and II inhibitors
KW - antifungal therapy
UR - http://www.scopus.com/inward/record.url?scp=85105834025&partnerID=8YFLogxK
U2 - 10.1093/femsyr/foab023
DO - 10.1093/femsyr/foab023
M3 - Artículo
C2 - 33837766
AN - SCOPUS:85105834025
SN - 1567-1356
VL - 21
JO - FEMS Yeast Research
JF - FEMS Yeast Research
IS - 3
M1 - foab023
ER -