Suramin action in African trypanosomes involves a RuvB-like DNA helicase
Suramin is one of the oldest drugs in use today. It is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense, and it is also used for surra in camels caused by Trypanosoma evansi. Yet despite one hundred years of use, suramin&...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320723000301 |
| _version_ | 1827591179181490176 |
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| author | Anna Albisetti Silvan Hälg Martin Zoltner Pascal Mäser Natalie Wiedemar |
| author_facet | Anna Albisetti Silvan Hälg Martin Zoltner Pascal Mäser Natalie Wiedemar |
| author_sort | Anna Albisetti |
| collection | DOAJ |
| description | Suramin is one of the oldest drugs in use today. It is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense, and it is also used for surra in camels caused by Trypanosoma evansi. Yet despite one hundred years of use, suramin's mode of action is not fully understood. Suramin is a polypharmacological molecule that inhibits diverse proteins. Here we demonstrate that a DNA helicase of the pontin/ruvB-like 1 family, termed T. brucei RuvBL1, is involved in suramin resistance in African trypanosomes. Bloodstream-form T. b. rhodesiense under long-term selection for suramin resistance acquired a homozygous point mutation, isoleucine-312 to valine, close to the ATP binding site of T. brucei RuvBL1. The introduction of this missense mutation, by reverse genetics, into drug-sensitive trypanosomes significantly decreased their sensitivity to suramin. Intriguingly, the corresponding residue of T. evansi RuvBL1 was found mutated in a suramin-resistant field isolate, in that case to a leucine. RuvBL1 (Tb927.4.1270) is predicted to build a heterohexameric complex with RuvBL2 (Tb927.4.2000). RNAi-mediated silencing of gene expression of either T. brucei RuvBL1 or RuvBL2 caused cell death within 72 h. At 36 h after induction of RNAi, bloodstream-form trypanosomes exhibited a cytokinesis defect resulting in the accumulation of cells with two nuclei and two or more kinetoplasts. Taken together, these data indicate that RuvBL1 DNA helicase is involved in suramin action in African trypanosomes. |
| first_indexed | 2024-03-09T01:28:10Z |
| format | Article |
| id | doaj.art-3beabf9372d546fc86fc9893d69c7c1e |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-03-09T01:28:10Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-3beabf9372d546fc86fc9893d69c7c1e2023-12-10T06:14:47ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072023-12-01234453Suramin action in African trypanosomes involves a RuvB-like DNA helicaseAnna Albisetti0Silvan Hälg1Martin Zoltner2Pascal Mäser3Natalie Wiedemar4Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland; University of Basel, Petersplatz 1, 4001, Basel, SwitzerlandSwiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland; University of Basel, Petersplatz 1, 4001, Basel, SwitzerlandDepartment of Parasitology, Faculty of Science, Charles University in Prague, Biocev, Vestec, Czech RepublicSwiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland; University of Basel, Petersplatz 1, 4001, Basel, SwitzerlandSwiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland; University of Basel, Petersplatz 1, 4001, Basel, Switzerland; Corresponding author. Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland.Suramin is one of the oldest drugs in use today. It is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense, and it is also used for surra in camels caused by Trypanosoma evansi. Yet despite one hundred years of use, suramin's mode of action is not fully understood. Suramin is a polypharmacological molecule that inhibits diverse proteins. Here we demonstrate that a DNA helicase of the pontin/ruvB-like 1 family, termed T. brucei RuvBL1, is involved in suramin resistance in African trypanosomes. Bloodstream-form T. b. rhodesiense under long-term selection for suramin resistance acquired a homozygous point mutation, isoleucine-312 to valine, close to the ATP binding site of T. brucei RuvBL1. The introduction of this missense mutation, by reverse genetics, into drug-sensitive trypanosomes significantly decreased their sensitivity to suramin. Intriguingly, the corresponding residue of T. evansi RuvBL1 was found mutated in a suramin-resistant field isolate, in that case to a leucine. RuvBL1 (Tb927.4.1270) is predicted to build a heterohexameric complex with RuvBL2 (Tb927.4.2000). RNAi-mediated silencing of gene expression of either T. brucei RuvBL1 or RuvBL2 caused cell death within 72 h. At 36 h after induction of RNAi, bloodstream-form trypanosomes exhibited a cytokinesis defect resulting in the accumulation of cells with two nuclei and two or more kinetoplasts. Taken together, these data indicate that RuvBL1 DNA helicase is involved in suramin action in African trypanosomes.http://www.sciencedirect.com/science/article/pii/S2211320723000301Trypanosoma bruceiTrypanosoma evansiSuraminDrug-resistanceRuvB-like 1 DNA helicaseDrug target |
| spellingShingle | Anna Albisetti Silvan Hälg Martin Zoltner Pascal Mäser Natalie Wiedemar Suramin action in African trypanosomes involves a RuvB-like DNA helicase International Journal for Parasitology: Drugs and Drug Resistance Trypanosoma brucei Trypanosoma evansi Suramin Drug-resistance RuvB-like 1 DNA helicase Drug target |
| title | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
| title_full | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
| title_fullStr | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
| title_full_unstemmed | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
| title_short | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
| title_sort | suramin action in african trypanosomes involves a ruvb like dna helicase |
| topic | Trypanosoma brucei Trypanosoma evansi Suramin Drug-resistance RuvB-like 1 DNA helicase Drug target |
| url | http://www.sciencedirect.com/science/article/pii/S2211320723000301 |
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