Antimalarialpyronaridine resistance may be associated with elevated MDR-1 gene expression profiles but not point mutation in Plasmodium bergheiANKA isolates

Abstract

Theselectionofresistance is inevitable whenever chemotherapy isnecessaryforpathogencontrol. Notably, Plasmodiumfalciparum has developed multifacetedmeans to overcomethetoxicityof nearly allantimalarial medicines. To bypass this challenge,not only should novel drugs be developed, but the resistance mechanisms tonewandexisting drugs need should be fullyexplored.Pyronaridine is a companion drug inPyramax®, a blend of artesunate (ASN)-pyronaridine (PRD) whichistheWHOprequalifiedalternative for malariatreatment in the Africansetting. However, half-life mismatch predisposes thePRDto swiftemergence of resistanceespeciallyin high malaria transmission settings. However, there are no well-characterized PRD-resistant parasite lines. Previously, stable PRD-resistant P. bergheiANKA lines were selected by in vivo drug pressure and preliminary results showed cross-resistance with quinolines, therefore, hypothetically theactivityof PRDand chloroquine or other quinolinesmay be comparable, hence, the resistance mechanisms may be parallel. Consequently, genetic polymorphisms and expressionprofiles of PbMDR-1 that could be associated with pyronaridine resistance wereexamined by PCR amplification, sequencingand transcript quantification byRT-qPCR.The transcripts level increased during resistanceselectionwhiletranslated PbMDR-1sequence alignment of PRD-sensitive and PRD-resistant was the same, theexpressionmay be linked toPRD resistance but not mutations