Drug action and resistance in malaria parasites: experimental genetics models and biochemical features of fast acting novel antimalarials

Simwela, Nelson Victor (2020) Drug action and resistance in malaria parasites: experimental genetics models and biochemical features of fast acting novel antimalarials. PhD thesis, University of Glasgow.

Abstract

Resistance to antimalarial drugs inevitably follows their deployment in malaria endemic parts of the world. For instance, current malaria control efforts which significantly rely on artemisinin combination therapies (ACTs) are being threatened by the emergence of resistance to artemisinins and ACTs. Understanding the role of genetic determinants of artemisinin resistance is therefore important for implementation of mitigation strategies. Moreover, elucidating the mode of action for drugs that are in advanced stages of development is specifically critical as drug resistance mechanisms can be prospectively predicted and possible means of surveillance put in place.

In the present work, CRISPR-Cas9 genome editing has been used to engineer candidate artemisinin resistance mutations (Kelch13 and UBP-1) in the rodent malaria parasite Plasmodium berghei. The role of these mutations in mediating artemisinin (and chloroquine) resistance under both in vitro and in vivo conditions has been assessed which up until now, has either remained un-validated (UBP-1) or debated (Kelch13, under in vivo conditions) in human infecting Plasmodium falciparum. The results have provided an in vivo model for understanding and validating artemisinin resistance phenotypes which just like their Plasmodium falciparum equivalents do not just mediate resistance phenotypes, but also carry accompanying fitness costs.

In addition to the above findings, biochemical and drug inhibition studies have been carried out to demonstrate that small molecule inhibitors targeting ubiquitin hydrolases (to which UBP-1 is a class member) display activity in human and rodent infecting malaria parasites in vitro and in vivo. These inhibitors also show evidence of ability to potentiate artemisinin action which can be exploited to overcome the emerging resistance as combination partner drugs. Untargeted metabolomic screens have also been used to characterize the mode of action of lead antimalarial drug candidates that are emerging from the Novartis Institute of Tropical Diseases drug discovery pipeline. A common biochemical and metabolic profile of these compounds which display a very fast parasite killing rate is presented and can hopefully be used to identify compounds that can achieve a similar feat. Moreover, these profiles have pointed to possible mode of action for novel drugs whose mechanistic mode of parasite killing is still unknown or disputed.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Antimalarial drugs, mode of action, resistance, genetics models, biochemistry, metabolomics.
• Subjects: Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Parasitology
• Funder's Name: Wellcome Trust (WELLCOTR), Commonwealth Scholarship Commission in the UK (CSCUK)
• Supervisor's Name: Waters, Professor Andy and Barrett, Professor Mike
• Date of Award: 2020
• Depositing User: Dr Nelson Simwela
• Unique ID: glathesis:2020-81876
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 Dec 2020 17:02
• Last Modified: 16 Sep 2022 15:52
• Thesis DOI: 10.5525/gla.thesis.81876
• URI: https://theses.gla.ac.uk/id/eprint/81876

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