Investigating novel mechanisms of drug resistance in Plasmodium falciparum

Abstract

Due to widespread drug resistance undermining antimalarial eradication efforts, there is an urgency to develop new drugs. Drug repurposing was adopted, with drug L selected as a candidate drug. Lack of observable hemozoin, which is a unique resistant phenotype, and discovery of A257T mutation in Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene in resistant clones prompted investigation into characteristics of L resistance and validation of A257T as a molecular marker of resistance. Our findings indicate L resistance is characterized by a gentle dose response curve shape, lack of 100% inhibition, and reduction in replication rate. This study proved that A257T was not a molecular marker of resistance. Moreover, we showed that pfmdr1 copy number variation (CNV) did not play a role in L resistance mechanism, unlike in many other antimalarials, highlighting that a point mutation is likely the genetic cause of L resistance. Additional findings showed the involvement of strain-dependent genetic background in conferring L resistance. Understanding the basis for L resistance plays an essential role in determining if new antimalarials have resistance-refractory properties as well as improve epidemiologic surveillance on prevalence of drug resistant parasites. Additionally, it allows for the evaluation of L on its suitability as an antimalarial.