Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites

Claudia L L Valentim, Donato Cioli, Fréd́eric D. Chevalier, Xiaohang Cao, Alexander B. Taylor, Stephen P. Holloway, Livia Pica-Mattoccia, Alessandra Guidi, Annalisa Basso, Isheng J. Tsai, Matthew Berriman, Claudia Carvalho-Queiroz, Marcio Almeida, Hector Aguilar, Doug E. Frantz, P. John Hart, Philip T Loverde, Timothy J C Anderson

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ∼500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.

Original languageEnglish (US)
Pages (from-to)1385-1389
Number of pages5
JournalScience
Volume342
Issue number6164
DOIs
StatePublished - 2013

Fingerprint

Oxamniquine
Drug Resistance
Molecular Biology
Parasites
Schistosoma mansoni
Pharmaceutical Preparations
Sulfotransferases
Trematoda
Chromosomes, Human, Pair 6
Helminths
Chromosome Mapping
Quantitative Trait Loci
Schistosomiasis
RNA Interference
Drug Interactions
Brazil
Mutation
Genes
Proteins

ASJC Scopus subject areas

  • General

Cite this

Valentim, C. L. L., Cioli, D., Chevalier, F. D., Cao, X., Taylor, A. B., Holloway, S. P., ... Anderson, T. J. C. (2013). Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites. Science, 342(6164), 1385-1389. https://doi.org/10.1126/science.1243106

Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites. / Valentim, Claudia L L; Cioli, Donato; Chevalier, Fréd́eric D.; Cao, Xiaohang; Taylor, Alexander B.; Holloway, Stephen P.; Pica-Mattoccia, Livia; Guidi, Alessandra; Basso, Annalisa; Tsai, Isheng J.; Berriman, Matthew; Carvalho-Queiroz, Claudia; Almeida, Marcio; Aguilar, Hector; Frantz, Doug E.; Hart, P. John; Loverde, Philip T; Anderson, Timothy J C.

In: Science, Vol. 342, No. 6164, 2013, p. 1385-1389.

Research output: Contribution to journalArticle

Valentim, CLL, Cioli, D, Chevalier, FD, Cao, X, Taylor, AB, Holloway, SP, Pica-Mattoccia, L, Guidi, A, Basso, A, Tsai, IJ, Berriman, M, Carvalho-Queiroz, C, Almeida, M, Aguilar, H, Frantz, DE, Hart, PJ, Loverde, PT & Anderson, TJC 2013, 'Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites', Science, vol. 342, no. 6164, pp. 1385-1389. https://doi.org/10.1126/science.1243106
Valentim CLL, Cioli D, Chevalier FD, Cao X, Taylor AB, Holloway SP et al. Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites. Science. 2013;342(6164):1385-1389. https://doi.org/10.1126/science.1243106
Valentim, Claudia L L ; Cioli, Donato ; Chevalier, Fréd́eric D. ; Cao, Xiaohang ; Taylor, Alexander B. ; Holloway, Stephen P. ; Pica-Mattoccia, Livia ; Guidi, Alessandra ; Basso, Annalisa ; Tsai, Isheng J. ; Berriman, Matthew ; Carvalho-Queiroz, Claudia ; Almeida, Marcio ; Aguilar, Hector ; Frantz, Doug E. ; Hart, P. John ; Loverde, Philip T ; Anderson, Timothy J C. / Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites. In: Science. 2013 ; Vol. 342, No. 6164. pp. 1385-1389.
@article{fd077f6fa4594ea0b4d96a875c26ca97,
title = "Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites",
abstract = "Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ∼500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99{\%} of schistosomiasis cases worldwide.",
author = "Valentim, {Claudia L L} and Donato Cioli and Chevalier, {Fr{\'e}d́eric D.} and Xiaohang Cao and Taylor, {Alexander B.} and Holloway, {Stephen P.} and Livia Pica-Mattoccia and Alessandra Guidi and Annalisa Basso and Tsai, {Isheng J.} and Matthew Berriman and Claudia Carvalho-Queiroz and Marcio Almeida and Hector Aguilar and Frantz, {Doug E.} and Hart, {P. John} and Loverde, {Philip T} and Anderson, {Timothy J C}",
year = "2013",
doi = "10.1126/science.1243106",
language = "English (US)",
volume = "342",
pages = "1385--1389",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6164",

}

TY - JOUR

T1 - Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites

AU - Valentim, Claudia L L

AU - Cioli, Donato

AU - Chevalier, Fréd́eric D.

AU - Cao, Xiaohang

AU - Taylor, Alexander B.

AU - Holloway, Stephen P.

AU - Pica-Mattoccia, Livia

AU - Guidi, Alessandra

AU - Basso, Annalisa

AU - Tsai, Isheng J.

AU - Berriman, Matthew

AU - Carvalho-Queiroz, Claudia

AU - Almeida, Marcio

AU - Aguilar, Hector

AU - Frantz, Doug E.

AU - Hart, P. John

AU - Loverde, Philip T

AU - Anderson, Timothy J C

PY - 2013

Y1 - 2013

N2 - Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ∼500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.

AB - Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ∼500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.

UR - http://www.scopus.com/inward/record.url?scp=84890114435&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890114435&partnerID=8YFLogxK

U2 - 10.1126/science.1243106

DO - 10.1126/science.1243106

M3 - Article

VL - 342

SP - 1385

EP - 1389

JO - Science

JF - Science

SN - 0036-8075

IS - 6164

ER -