Abstract
The selection of resistance is inevitable whenever chemotherapy is necessary for pathogen control. Notably, Plasmodium falciparum has developed multifaceted means to overcome the toxicity of nearly all antimalarial medicines. To bypass this challenge, not only should novel drugs be developed, but the resistance mechanisms to new and existing drugs need should be fully explored. Pyronaridine is a companion drug in Pyramax®, a blend of artesunate (ASN)-pyronaridine (PRD) which is the WHO prequalified alternative for malaria treatment in the African setting. However, half-life mismatch predisposes the PRD to swift emergence of resistance especially in high malaria transmission settings. However, there are no well-characterized PRD-resistant parasite lines. Previously, stable PRD- resistant P. berghei ANKA lines were selected by in vivo drug pressure and preliminary results showed cross-resistance with quinolines, therefore, hypothetically the activity of PRD and chloroquine or other quinolines may be comparable, hence, the resistance mechanisms may be parallel. Consequently, genetic polymorphisms and expression profiles of PbMDR-1 that could be associated with pyronaridine resistance were examined by PCR amplification, sequencing and transcript quantification by RT-qPCR. The transcripts level increased during resistance selection while translated PbMDR-1 sequence alignment of PRD-sensitive and PRD-resistant was the same, the expression may be linked to PRD resistance but not mutations. Key words: Quinolines, malaria, Pyronaridine, Pyramax®, resistance, expression, MDR-1 gene.
Highlights
Malaria is one of the most devastating infectious diseases faced by the humanity in the 21st century
The goal of this study is to identify genetic polymorphisms and expression profiles that could be associated with PRD resistance in selected genes associated with quinoline or any other anti-malarial drugs- preliminarily the multi-drug resistant gene 1 (MDR-1)
To explore the potential modulatory and compensatory role of MDR-1, the mRNA transcript level was measured. These results demonstrated that the transcripts level increased during selection of pyronaridine resistance (Figure 2), while the translated PbMDR-1sequence alignment of PRD-sensitive and PRD-resistant was 100% identical (Supplementary Figure S2)
Summary
Malaria is one of the most devastating infectious diseases faced by the humanity in the 21st century. One such strategy for plummeting the malaria prevalence is the usage of twin- or triple-anti-malarial drug combinations, which is thought to protect each drug from the development of resistance and reduce the overall transmission of malaria (Dipanjan et al, 2017; Tse et al, 2019; Mishra et al, 2017). This emergence of parasite resistance to some forms of ACT indicates that novel compounds and combinations must be discovered and developed (Ouji et al, 2018)
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