Investigating novel mechanisms of drug resistance in Plasmodium falciparum

• Main Author: Ng, Shyan Poh Shuang
• Other Authors: Peter Preiser
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2021
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/153285
• Institution: Nanyang Technological University

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.