MRPA-independent mechanisms of antimony resistance in Leishmania infantum
| Autor: | Victoria Wagner, Marc Ouellette, Christopher Fernandez-Prada, Noélie Douanne, Gaétan Roy, Philippe Leprohon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Antimony Genes Protozoan 030231 tropical medicine Mutant Antiprotozoal Agents Protozoan Proteins ATP-binding cassette transporter Drug resistance Article Gene disruption lcsh:Infectious and parasitic diseases 03 medical and health sciences Dogs 0302 clinical medicine Animals Humans Pharmacology (medical) lcsh:RC109-216 Leishmania infantum Amastigote Leishmaniasis Gene Pharmacology Genetics Whole-genome sequencing Whole Genome Sequencing biology Membrane Transport Proteins MRPA biology.organism_classification Leishmania Multidrug Resistance-Associated Protein 2 3. Good health 030104 developmental biology Infectious Diseases Mutation Antimonial ATP-Binding Cassette Transporters Parasitology Serine O-Acetyltransferase |
| Zdroj: | International Journal for Parasitology: Drugs and Drug Resistance, Vol 13, Iss, Pp 28-37 (2020) International Journal for Parasitology: Drugs and Drug Resistance |
| ISSN: | 2211-3207 |
| Popis: | Control of both human and canine leishmaniasis is based on a very short list of chemotherapeutic agents, headed by antimonial derivatives (Sb). The utility of these molecules is severely threatened by high rates of drug resistance. The ABC transporter MRPA is one of the few key Sb resistance proteins described to date, whose role in detoxification has been thoroughly studied in Leishmania parasites. Nonetheless, its rapid amplification during drug selection complicates the discovery of other mechanisms potentially involved in Sb resistance. In this study, stepwise drug-resistance selection and next-generation sequencing were combined in the search for novel Sb-resistance mechanisms deployed by parasites when MRPA is abolished by targeted gene disruption. The gene mrpA is not essential in L. infantum, and its disruption leads to an Sb hypersensitive phenotype in both promastigotes and amastigotes. Five independent mrpA−/- mutants were selected for antimony resistance. These mutants displayed major changes in their ploidy, as well as extrachromosomal linear amplifications of the subtelomeric region of chromosome 23, which includes the genes coding for ABCC1 and ABCC2. Overexpression of ABCC2, but not of ABCC1, resulted in increased Sb tolerance in the mrpA−/- mutant. SNP analyses revealed three different heterozygous mutations in the gene coding for a serine acetyltransferase (SAT) involved in de novo cysteine synthesis in Leishmania. Overexpression of satQ390K, satG321R and satG325R variants led to a 2–3.2 -fold increase in Sb resistance in mrpA−/- parasites. Only satG321R and satG325R induced increased Sb resistance in wild-type parasites. These results reinforce and expand knowledge on the complex nature of Sb resistance in Leishmania parasites. Graphical abstract Image 1 Highlights • mrpA is not an essential gene in Leishmania infantum parasites. • Disruption of mrpA leads to an antimony-hypersensitive phenotype in promastigotes and amastigotes. • L. infantum deploys secondary survival mechanisms to increase antimony tolerance in the absence of MRPA. • Overexpression of ABCC2 confers resistance to antimony in mrpA null mutants. • Different mutations in the sat gene confer resistance to antimony. |
| Databáze: | OpenAIRE |
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