Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials

• Published in: Trends in parasitology 2021-08, Vol.37 (8), p.709-721
• Main Authors: Duffey, Maëlle, Blasco, Benjamin, Burrows, Jeremy N., Wells, Timothy N.C., Fidock, David A., Leroy, Didier
• Format: Article
• Language: English
• Subjects: drug discovery; malaria; Plasmodium falciparum; resistance
• ISSN: 1471-4922; 1471-5007
• DOI: 10.1016/j.pt.2021.04.006

Strategies to counteract or prevent emerging drug resistance are crucial for the design of next-generation antimalarials. In the past, resistant parasites were generally identified following treatment failures in patients, and compounds would have to be abandoned late in development. An early understanding of how candidate therapeutics lose efficacy as parasites evolve resistance is important to facilitate drug design and improve resistance detection and monitoring up to the postregistration phase. We describe a new strategy to assess resistance to antimalarial compounds as early as possible in preclinical development by leveraging tools to define the Plasmodium falciparum resistome, predict potential resistance risks of clinical failure for candidate therapeutics, and inform decisions to guide antimalarial drug development. Artemisinin-based combination therapies are first-line treatments for uncomplicated Plasmodium falciparum malaria. However, during the past decade, partial resistance to artemisinins, mediated by PfK13 mutations, has spread across Southeast Asia and emerged in South America, the Western Pacific, and Africa. The emergence of resistance to partner drugs has led to frequent treatment failures in Southeast Asia.The development of new antimalarials with a high barrier to resistance is an urgent and critical need and should be guided by a standardized and streamlined assessment of potential resistance liabilities.We propose a novel strategy to assess drug resistance risks early in the drug development pipeline and to help prioritize novel antimalarials with a low potential for resistance. We also review approaches to gain a greater understanding of resistance risks and guide future combination decisions.