Selection of cytochrome b mutants is rare among plasmodium falciparum patients failing treatment with atovaquone- proguanil in cambodia

Jessica T. Lin*, Andreea Waltmann, Kara A. Moser, Zackary Park, Yu Bin Na, Ozkan Aydemir, Nicholas F. Brazeau, Panita Gosi, Patrick W. Marsh, Meredith S. Muller, Michele Spring, Somethy Sok, Jeffrey A. Bailey, David L. Saunders, Chanthap Lon, Mariusz Wojnarski

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Atovaquone-proguanil remains effective against multidrug-resistant Plasmodium falciparum in Southeast Asia, but resistance is mediated by a single point mutation in cytochrome b (cytb) that can arise during treatment. Among 14 atovaquone- proguanil treatment failures in a clinical trial in Cambodia, only one recrudescence harbored the cytb mutation Y268C. Deep sequencing did not detect the mutation at baseline or in the first 3 days of treatment, suggesting that it arose de novo. Further sequencing across cytb similarly found no low-frequency cytb mutations that were up-selected from baseline to recrudescence. Copy number amplification in dihydroorotate dehydrogenase (DHODH) and cytb as markers of atovaquone tolerance was also absent. Cytb mutation played a minor role in atovaquone-proguanil treatment failures in an active comparator clinical trial.

Original languageEnglish
Article numbere01249-20
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number3
DOIs
StatePublished - Mar 2021
Externally publishedYes

Keywords

  • Atovaquone-proguanil
  • Cytochrome b
  • Deep sequencing
  • Drug resistance
  • Malaria
  • Malarone
  • Plasmodium falciparum

Fingerprint

Dive into the research topics of 'Selection of cytochrome b mutants is rare among plasmodium falciparum patients failing treatment with atovaquone- proguanil in cambodia'. Together they form a unique fingerprint.

Cite this