Biology subjects

Arbon, D.

Publications and source records attributed to Arbon, D..

2 recordsLinked to original sources

bioRxiv2022

Repurposing of mitochondria-targeted tamoxifen: Novel anti-cancer drug exhibits potent activity against major protozoan and fungal pathogens.

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 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. Author SummaryMitoTam, a mitochondrially targeted analog of tamoxifen, is a promising anti-cancer candidate drug acting by accumulating in and destabilizing cell mitochondria. In this study, we analyze its effect on a wide range of evolutionarily distinct and medically important pathogens. These include a) pathogenic fungi, Candida albicans, and Cryptococcus neoformans, ubiquitous opportunistic pathogens that cause life-threatening diseases in immunocompromised or immunologically deficient individuals; b) Plasmodium falciparum, the causative agent of human malaria; and c) several species of trypanosomatid parasites such as Trypanosoma cruzi, responsible for deadly Chagas disease in South America, Trypanosoma brucei, the causative agent of sleeping sickness in Africa, and Leishmania, the etiological agent of leishmaniasis, a spectrum of diseases ranging from usually self-healing but potentially disfiguring cutaneous and mucocutaneous leishmaniasis, to visceral leishmaniasis, which is invariably fatal if left untreated. We show that MitoTam efficiently kills these parasites in laboratory conditions and in the case of trypanosomes and leishmaniases suppress or at least slow down the infection in mouse model.

microbiology↗

bioRxiv2019

Adaptive iron utilization compensates for the lack of an inducible uptake system in Naegleria fowleri and represents a potential target for therapeutic intervention

Warm fresh water is a natural habitat for many single-celled organisms, including protozoan parasites such as the infamous brain-eating amoeba, Naegleria fowleri, which can become pathogenic for mammals, including humans. The condition caused by N. fowleri is known as primary amoebic meningoencephalitis, which is a generic and usually fatal infection of the brain with rapid onset. One of the important factors influencing a wide spectrum of pathogens, including N. fowleri, is the bioavailability of iron in the environment. The strategy of withholding iron evolved in mammalian hosts, and the different strategies of pathogens to obtain it are an important part of host-parasite interactions.\n\nIn the present study, we employ different biochemical and analytical methods to explore the effect of decreased iron availability on the cellular processes of N. fowleri. We show that under iron starvation, nonessential, iron-dependent, mostly cytosolic pathways in N. fowleri are downregulated, while the metal is utilized in the mitochondria to maintain vital respiratory processes. Surprisingly, N. fowleri fails to respond to acute shortages of iron by the induction of a reductive iron uptake system that seems to be the main iron-obtaining strategy of the parasite. Our work aims to demonstrate the importance of mitochondrial iron in the biology of N. fowleri and to explore the plausibility of exploiting it as a potential target for therapeutic interference.\n\nAuthor SummaryNaegleria fowleri is undoubtedly one of the deadliest parasites of humans, hence the name \"brain-eating amoeba\". Being dangerous, but rare, it may be regarded as a highly understudied pathogen of humans. Unfortunately, the symptoms of primary amoebic meningoencephalitis may be confused with much more common bacterial meningoencephalitis; therefore, it is quite probable that many infections caused by N. fowleri have been misdiagnosed as bacterial infections without further inquiry. In many cases, fast diagnosis is vital for commencing the correct therapy, and even then, complete success of the treatment is very rare. Our laboratory focuses on the uptake and intracellular metabolism of metals in unicellular eukaryotes, so we decided to explore the biology of N. fowleri from this aspect. Changes in the proteome, as a direct effect of iron-deficient conditions, were described, and these data were used to further explore the ways in which N. fowleri responds to these conditions on a cellular level and how its biology changes. Based on these findings, we propose that the struggle of N. fowleri to obtain iron from its host could be exploited for therapeutic interference purposes in primary amoebic meningoencephalitis patients.

biochemistry↗