Surreal illustration of a malaria parasite with glowing mutations, representing drug resistance.

Decoding Malaria's Defenses: New Insights into Drug Resistance

Theo Raines in Health & Wellness September 2025 • 4 min read.

"Scientists uncover how malaria parasites develop resistance to a promising drug, paving the way for smarter treatment strategies."

Malaria continues to be a major global health challenge, with resistance to existing treatments hindering prevention and control efforts. The emergence of drug-resistant strains of Plasmodium falciparum, the parasite responsible for most malaria deaths, poses a significant threat. Therefore, there is urgent need to develop new antimalarial drugs and understand resistance mechanisms.

One promising drug candidate, DSM265, inhibits dihydroorotate dehydrogenase (DHODH), an enzyme essential for the parasite's survival. DSM265 has shown good safety and efficacy in early clinical trials; however, like other antimalarials, the parasite can develop resistance over time.

To prepare for this inevitability, researchers have investigated how P. falciparum develops resistance to DSM265. By studying parasites under drug pressure in the lab, they have identified specific genetic mutations that reduce the drug's effectiveness. These findings provide valuable insights for designing strategies to prolong the lifespan of DSM265 and other next-generation antimalarials.

Unlocking the Genetic Secrets of DSM265 Resistance

Surreal illustration of a malaria parasite with glowing mutations, representing drug resistance.

Scientists conducted in vitro experiments, exposing P. falciparum parasites to gradually increasing concentrations of DSM265. They then analyzed the parasites that survived, pinpointing mutations in the Pfdhodh gene, which encodes the DHODH enzyme. These mutations allowed the parasites to thrive even in the presence of the drug.

The study identified five distinct amino acid changes in the DHODH enzyme that conferred resistance to DSM265. These mutations altered the shape of the enzyme's active site, reducing DSM265's ability to bind and inhibit its function. Interestingly, parasites with these mutations remained fully sensitive to atovaquone, another antimalarial drug, suggesting that combining DSM265 with other drugs could help prevent resistance.

G181C: A mutation at position 181, changing glycine to cysteine.
C276F/Y: Changes at position 276, substituting cysteine with either phenylalanine or tyrosine. This mutation was also observed in a clinical trial.
E182D: A change at position 182, from glutamic acid to aspartic acid.
R265G: A mutation at position 265, altering arginine to glycine.
L531F: A change at position 531, from leucine to phenylalanine.

Further structural analysis revealed how these mutations impact DSM265 binding. For example, the C276F mutation, which was also found in parasites from a patient who experienced treatment failure, causes a shift in nearby residues, effectively shrinking the drug-binding pocket. This makes it harder for DSM265 to attach to the enzyme and exert its inhibitory effect. These detailed structural insights can guide the development of new drugs that can overcome these resistance mechanisms.

Future Directions: Smarter Drugs, Smarter Combinations

This research underscores the importance of developing DSM265 as part of a combination therapy with other antimalarial agents. By combining drugs with different mechanisms of action, it is possible to slow down or prevent the emergence of resistance.

Moreover, the identification of specific resistance mutations provides valuable markers for monitoring drug effectiveness in the field. Diagnostic tests can be developed to detect these mutations, allowing clinicians to tailor treatment strategies and avoid using drugs that are likely to be ineffective.

Ultimately, a deeper understanding of the mechanisms of drug resistance is crucial for developing sustainable antimalarial therapies and controlling this deadly disease. By staying one step ahead of the parasite, scientists can help ensure that effective treatments remain available for those who need them most.

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This article is based on research published under:

DOI-LINK: 10.1021/acsinfecdis.8b00211, Alternate LINK

Title: Identification And Mechanistic Understanding Of Dihydroorotate Dehydrogenase Point Mutations In Plasmodium Falciparum That Confer In Vitro Resistance To The Clinical Candidate Dsm265

Subject: Infectious Diseases

Journal: ACS Infectious Diseases

Publisher: American Chemical Society (ACS)

Authors: John White, Satish K. Dhingra, Xiaoyi Deng, Farah El Mazouni, Marcus C. S. Lee, Gustavo A. Afanador, Aloysus Lawong, Diana R. Tomchick, Caroline L. Ng, Jade Bath, Pradipsinh K. Rathod, David A. Fidock, Margaret A. Phillips

Published: 2018-10-30

Everything You Need To Know

How does Plasmodium falciparum develop resistance to DSM265?

Resistance to DSM265 in Plasmodium falciparum arises due to specific genetic mutations in the Pfdhodh gene, which encodes the DHODH enzyme. The study identified five distinct amino acid changes: G181C, C276F/Y, E182D, R265G, and L531F. These mutations alter the shape of the DHODH enzyme's active site, hindering DSM265's ability to bind and inhibit the enzyme's function, thus reducing the drug's effectiveness.

What methods did researchers use to uncover the resistance mechanisms to DSM265?

Researchers exposed Plasmodium falciparum parasites to increasing concentrations of DSM265 in vitro. By analyzing the surviving parasites, they pinpointed mutations in the Pfdhodh gene. Further structural analysis revealed how mutations like C276F, found in clinical trial failures, shrink the drug-binding pocket, making it difficult for DSM265 to attach and inhibit the DHODH enzyme.

Which specific mutations in the DHODH enzyme confer resistance to DSM265?

The mutations identified include G181C (glycine to cysteine), C276F/Y (cysteine to phenylalanine or tyrosine), E182D (glutamic acid to aspartic acid), R265G (arginine to glycine), and L531F (leucine to phenylalanine). Each of these mutations alters the active site of the DHODH enzyme, reducing the binding affinity of DSM265.

Why is combination therapy important in combating malaria drug resistance, particularly concerning DSM265?

Combining DSM265 with other antimalarial drugs like atovaquone is a promising strategy. The study found that parasites resistant to DSM265 remained sensitive to atovaquone. Combination therapies using drugs with different mechanisms of action can slow down or prevent the emergence of resistance, prolonging the lifespan and effectiveness of antimalarial treatments. This approach leverages the different vulnerabilities of the parasite, making it more difficult for resistance to develop.

What are the implications of discovering the genetic mechanisms behind DSM265 resistance for future antimalarial drug development?

The discovery of specific mutations (G181C, C276F/Y, E182D, R265G, L531F) that confer resistance to DSM265 is crucial for developing next-generation antimalarials. Understanding how these mutations alter the DHODH enzyme's structure and function allows scientists to design new drugs that can overcome these resistance mechanisms. Furthermore, this knowledge informs the strategic use of combination therapies to prevent or delay the onset of resistance, ensuring more effective malaria treatment and control.