The problem of antimalarial resistance and its implications for drug discovery

ABSTRACT

Introduction

Malaria remains a devastating infectious disease with hundreds of thousands of casualties each year. Antimalarial drug resistance has been a threat to malaria control and elimination for many decades and is still of concern today. Despite the continued effectiveness of current first-line treatments, namely artemisinin-based combination therapies, the emergence of drug-resistant parasites in Southeast Asia and even more alarmingly the occurrence of resistance mutations in Africa is of great concern and requires immediate attention.

Areas Covered

A comprehensive overview of the mechanisms underlying the acquisition of drug resistance in Plasmodium falciparum is given. Understanding these processes provides valuable insights that can be harnessed for the development and selection of novel antimalarials with reduced resistance potential. Additionally, strategies to mitigate resistance to antimalarial compounds on the short term by using approved drugs are discussed.

Expert opinion

While employing strategies that utilize already approved drugs may offer a prompt and cost-effective approach to counter antimalarial drug resistance, it is crucial to recognize that only continuous efforts into the development of novel antimalarial drugs can ensure the successful treatment of malaria in the future. Incorporating resistance propensity assessment during this developmental process will increase the likelihood of effective and enduring malaria treatments.

KEYWORDS:

• Plasmodium falciparum
• antimalarial drug resistance
• artemisinin-based combination therapies
• antimalarial drug discovery
• irresistibles

Article highlights

• Robust pipelines for antimalarial drug development have been established in recent years.

• In vitro evolution and whole-genome sequencing approaches allow to investigate resistance potential and mechanisms early on during drug development.

• Controlled human malaria infection trials could accelerate drug development in the future and allow to estimate the in vivo resistance potential of novel antimalarial compounds.

• Triple artemisinin-based combination therapies and alternating deployment of approved ACTs have the potential to dampen resistance development and to increase treatment efficacy in areas in which multidrug-resistant parasite strains are transmitted.

• Many promising novel antimalarials are currently in pre-clinical development or being used in patient exploratory trials.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are funded by the Deutsche Forschungsgemeinschaft via grants 285846829 and 461708005.