Independence from Kinetoplast DNA Maintenance and Expression Is Associated with Multidrug Resistance in Trypanosoma brucei
            <i>In Vitro</i>

Gould, Matthew K.; Schnaufer, Achim

doi:10.1128/aac.00122-14

Cited by 30 publications

(52 citation statements)

References 31 publications

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“…However, the discovery in laboratory generated-dyskinetoplastic T. b. brucei of a compensating mutation in the nuclear genome-encoded γ-subunit of the mitochondrial ATP synthase (Dean et al 2013) meant that the kinetoplast has been resurrected as the potential drug target of diminazene. These dyskinetoplastic lines do indeed show significant in vitro resistance to diamidines (including diminazene aceturate) and phenanthridines (Gould and Schnaufer, 2014). Furamidine (DB75), a closely related diamidine, whose fluorescent properties enabled tracking of its cellular distribution, was shown to bind to T. b. brucei kDNA and nuclear DNA in situ , and also to accumulate in other organelles identified as acidocalcisomes (Mathis et al 2006).…”

Section: Veterinary Trypanocides: Dosage Pharmacokinetics Mode Of Amentioning

confidence: 99%

“…Linearization of kDNA minicircles in T. b. equiperdum following interaction of the drug with the kinetoplast was observed (Shapiro and Englund, 1990). Moreover, naturally occurring dyskinetoplastic T. b. evansi (Brun and Lun, 1994) and in vitro -generated T. b. brucei lacking a functional kinetoplast (Gould and Schnaufer, 2014) are highly resistant to the drug. Efficacy against some T. b. evansi strains might relate to these parasites retaining kDNA (albeit dispersed in dyskinetoplastidy) while others are akinetoplastic (i.e.…”

Section: Veterinary Trypanocides: Dosage Pharmacokinetics Mode Of Amentioning

confidence: 99%

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The animal trypanosomiases and their chemotherapy: a review

et al. 2016

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SUMMARYPathogenic animal trypanosomes affecting livestock have represented a major constraint to agricultural development in Africa for centuries, and their negative economic impact is increasing in South America and Asia. Chemotherapy and chemoprophylaxis represent the main means of control. However, research into new trypanocides has remained inadequate for decades, leading to a situation where the few compounds available are losing efficacy due to the emergence of drug-resistant parasites. In this review, we provide a comprehensive overview of the current options available for the treatment and prophylaxis of the animal trypanosomiases, with a special focus on the problem of resistance. The key issues surrounding the main economically important animal trypanosome species and the diseases they cause are also presented. As new investment becomes available to develop improved tools to control the animal trypanosomiases, we stress that efforts should be directed towards a better understanding of the biology of the relevant parasite species and strains, to identify new drug targets and interrogate resistance mechanisms.

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Section: Veterinary Trypanocides: Dosage Pharmacokinetics Mode Of Amentioning

confidence: 99%

Section: Veterinary Trypanocides: Dosage Pharmacokinetics Mode Of Amentioning

confidence: 99%

The animal trypanosomiases and their chemotherapy: a review

et al. 2016

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“…ISM, a phenanthridine related to ethidium bromide, is mainly used as a prophylactic against nagana disease in cattle, with millions of doses administered each year. This drug accumulates in the kinetoplast, and cells with mutations in the γ-subunit of ATP synthase are ISM resistant (5). Ethidium bromide has itself also been used against nagana.…”

Section: Significancementioning

confidence: 99%

Vacuolar ATPase depletion affects mitochondrial ATPase function, kinetoplast dependency, and drug sensitivity in trypanosomes

Baker

Hamilton

Wilkes

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Kinetoplastid parasites cause lethal diseases in humans and animals. The kinetoplast itself contains the mitochondrial genome, comprising a huge, complex DNA network that is also an important drug target. Isometamidium, for example, is a key veterinary drug that accumulates in the kinetoplast in African trypanosomes. Kinetoplast independence and isometamidium resistance are observed where certain mutations in the F 1 -γ-subunit of the two-sector F 1 F o -ATP synthase allow for F o -independent generation of a mitochondrial membrane potential. To further explore kinetoplast biology and drug resistance, we screened a genome-scale RNA interference library in African trypanosomes for isometamidium resistance mechanisms. Our screen identified 14 V-ATPase subunits and all 4 adaptin-3 subunits, implicating acidic compartment defects in resistance; V-ATPase acidifies lysosomes and related organelles, whereas adaptin-3 is responsible for trafficking among these organelles. Independent strains with depleted V-ATPase or adaptin-3 subunits were isometamidium resistant, and chemical inhibition of the V-ATPase phenocopied this effect. While drug accumulation in the kinetoplast continued after V-ATPase subunit depletion, acriflavine-induced kinetoplast loss was specifically tolerated in these cells and in cells depleted for adaptin-3 or endoplasmic reticulum membrane complex subunits, also identified in our screen. Consistent with kinetoplast dispensability, V-ATPase defective cells were oligomycin resistant, suggesting ATP synthase uncoupling and bypass of the normal F o -A6-subunit requirement; this subunit is the only kinetoplast-encoded product ultimately required for viability in bloodstream-form trypanosomes. Thus, we describe 30 genes and 3 protein complexes associated with kinetoplast-dependent growth. Mutations affecting these genes could explain natural cases of dyskinetoplasty and multidrug resistance. Our results also reveal potentially conserved communication between the compartmentalized two-sector rotary ATPases.brucei | mitochondrion | nagana | petite | samorin

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“…3C), yet both organisms can be killed by pentamidine. Moreover, dyskinetoplasic T. brucei, lacking the mitochondrial genome and its encoded ribosomes, remains quite sensitive to pentamidine (Damper and Patton, 1976;Gould and Schnaufer, 2014). Finally, since a single base change near the peptidyl transferase site of the mitochondrial ribosome can reduce the pentamidine sensitivity of S. cerevisiae, we might expect that such a mutation might also be commonly achievable within a large population of trypanosomes under high selection for pentamidine resistance across many millions of patients.…”

Section: Resultsmentioning

confidence: 96%

Mutation of the mitochondrial large ribosomal RNA can provide pentamidine resistance to Saccharomyces cerevisiae

2014

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Pentamidine is used to treat several trypanosomal diseases, as well as opportunistic infection by pathogenic fungi. However, the relevant targets of this drug are unknown. We isolated dominant mutations providing pentamidine resistance to Saccharomyces cerevisiae, one of which was localized to mitochondrial DNA. Next-generation sequencing revealed alteration of a widely conserved base at the peptidyl transferase center of the mitochondrial 21S ribosomal RNA. Our results provide a potential rationale for the toxicity of this drug to patients, and we discuss whether blockade of mitochondrial translation is the mechanism by which pathogenic fungi or protists are killed by pentamidine.

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Independence from Kinetoplast DNA Maintenance and Expression Is Associated with Multidrug Resistance in Trypanosoma brucei In Vitro

Cited by 30 publications

References 31 publications

The animal trypanosomiases and their chemotherapy: a review

The animal trypanosomiases and their chemotherapy: a review

Vacuolar ATPase depletion affects mitochondrial ATPase function, kinetoplast dependency, and drug sensitivity in trypanosomes

Mutation of the mitochondrial large ribosomal RNA can provide pentamidine resistance to Saccharomyces cerevisiae

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