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Repurposing of MitoTam: Novel Anti-Cancer Drug Candidate Exhibits Potent Activity against Major Protozoan and Fungal Pathogens

D. Arbon, K. Ženíšková, K. Šubrtová, J. Mach, J. Štursa, M. Machado, F. Zahedifard, T. Leštinová, C. Hierro-Yap, J. Neuzil, P. Volf, M. Ganter, M. Zoltner, A. Zíková, L. Werner, R. Sutak

. 2022 ; 66 (8) : e0072722. [pub] 20220720

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22024815
E-zdroje Online Plný text

NLK Free Medical Journals od 1972 do Před 6 měsíci
Freely Accessible Science Journals od 1995 do Před 6 měsíci
PubMed Central od 1972 do Před 6 měsíci
Europe PubMed Central od 1972 do Před 6 měsíci
Open Access Digital Library od 1972-01-01
Open Access Digital Library od 1972-01-01

Odkazy

PubMed 35856666
DOI 10.1128/aac.00727-22
Knihovny.cz E-zdroje

Many of the currently available anti-parasitic and anti-fungal frontline drugs have severe limitations, including adverse side effects, complex administration, and increasing occurrence of resistance. The discovery and development of new therapeutic agents is a costly and lengthy process. Therefore, repurposing drugs with already established clinical application offers an attractive, fast-track approach for novel treatment options. In this study, we show that the anti-cancer drug candidate MitoTam, a mitochondria-targeted analog of tamoxifen, efficiently eliminates a wide range of evolutionarily distinct pathogens in vitro, including pathogenic fungi, Plasmodium falciparum, and several species of trypanosomatid parasites, causative agents of debilitating neglected tropical diseases. MitoTam treatment was also effective in vivo and significantly reduced parasitemia of two medically important parasites, Leishmania mexicana and Trypanosoma brucei, in their respective animal infection models. Functional analysis in the bloodstream form of T. brucei showed that MitoTam rapidly altered mitochondrial functions, particularly affecting cellular respiration, lowering ATP levels, and dissipating mitochondrial membrane potential. Our data suggest that the mode of action of MitoTam involves disruption of the inner mitochondrial membrane, leading to rapid organelle depolarization and cell death. Altogether, MitoTam is an excellent candidate drug against several important pathogens, for which there are no efficient therapies and for which drug development is not a priority.

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