Arbon 2022 Antimicrob Agents Chemother

Arbon D, Ženíšková K, Šubrtová K, Mach J, Štursa J, Machado M, Zahedifard F, Leštinová T, Hierro-Yap C, Neuzil J, Volf P, Ganter M, Zoltner M, Zíková A, Werner L, Sutak R (2022) Repurposing of MitoTam: Novel anti-cancer drug candidate exhibits potent activity against major protozoan and fungal pathogens. https://doi.org/10.1128/aac.00727-22

» Antimicrob Agents Chemother 66:e0072722. PMID: 35856666 Open Access

Arbon Dominik, Zeniskova Katerina, Subrtova Karolina, Mach Jan, Stursa Jan, Machado Marta, Zahedifard Farnaz, Lestinova Tereza, Hierro-Yap Carolina, Neuzil Jiri, Volf Petr, Ganter Markus, Zoltner Martin, Zikova Alena, Werner Lukas, Sutak Robert (2022) Antimicrob Agents Chemother

Abstract: 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. • Keywords: Candida, Cryptococcus, Leishmania, Plasmodium, Trypanosoma, Drug, Mitochondria • Bioblast editor: Plangger M • O2k-Network Lab: CZ Prague Neuzil J, CZ Ceske Budejovice Zikova A

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Infectious 

Organism: Protists 

Preparation: Intact cells 

Pathway: Gp  HRR: Oxygraph-2k 

2022-08