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Combating antimicrobial resistance in malaria, HIV and tuberculosis

Nature Reviews Drug Discovery (2024)Cite this article

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Abstract

Antimicrobial resistance poses a significant threat to the sustainability of effective treatments against the three most prevalent infectious diseases: malaria, human immunodeficiency virus (HIV) infection and tuberculosis. Therefore, there is an urgent need to develop novel drugs and treatment protocols capable of reducing the emergence of resistance and combating it when it does occur. In this Review, we present an overview of the status and underlying molecular mechanisms of drug resistance in these three diseases. We also discuss current strategies to address resistance during the research and development of next-generation therapies. These strategies vary depending on the infectious agent and the array of resistance mechanisms involved. Furthermore, we explore the potential for cross-fertilization of knowledge and technology among these diseases to create innovative approaches for minimizing drug resistance and advancing the discovery and development of new anti-infective treatments. In conclusion, we advocate for the implementation of well-defined strategies to effectively mitigate and manage resistance in all interventions against infectious diseases. 

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Fig. 1: Comparison of drug resistance mechanisms across pathogens.
Fig. 2: Plasmodium life cycle and WHO-recommended antimalarial drugs.
Fig. 3: HIV intracellular replication cycle and most commonly used anti-HIV drugs.
Fig. 4: Mycobacterium tuberculosis life cycle and the WHO-recommended anti-tuberculosis drugs.
Fig. 5: Comparison of resistance management strategies for combating drug resistance.

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Acknowledgements

We thank P. Willis, S. Duparc and T. N. Wells for having carefully read and corrected the manuscript.

Author information

Author notes

  1. Maëlle Duffey

    Present address: The Global Antibiotic Research & Development Partnership, Geneva, Switzerland

Authors and Affiliations

  1. Medicines for Malaria Venture (MMV), R&D Department/Drug Discovery, ICC, Geneva, Switzerland

    Maëlle Duffey, Jeremy N. Burrows & Didier Leroy

  2. Department of Medicine/Infectious Diseases, Stanford University, Palo Alto, CA, USA

    Robert W. Shafer

  3. TB Alliance, New York NY, NY, USA

    Juliano Timm & Nader Fotouhi

  4. Alphina Therapeutics, New Haven, CT, USA

    Mark Cockett

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Contributions

M.D. and D.L. developed the concept, wrote the article and created the figures. R.W.S. and J.T. had a major contribution to improving the HIV and tuberculosis (TB) sections, respectively. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Didier Leroy.

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Competing interests

M.D. is an employee of the Global Antibiotic Research & Development Partnership (GARDP, Geneva) and was an employee of MMV when this Review was drafted. R.W.S. is professor of medicine at Stanford University. D.L. and J.N.B. are working for Medicines for Malaria Venture (MMV, Geneva). J.T. and N.F. are working for TB Alliance. M.C. is currently CEO & President of the company Alphina Therapeutics and consultant/adviser for Exavir Therapeutics. He is a former employee of ViiV Healthcare and a shareholder in GSK.

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Nature Reviews Drug Discovery thanks Richard Lee, Leann Tilley and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Pf3k genome database: https://www.malariagen.net/project/pf3k/

Glossary

Fitness cost of resistance

The capacity, or lack thereof, for a mutated drug-resistant pathogen to outcompete susceptible pathogens in the absence of the drug.

Frequency of resistance

The frequency at which a detectable mutant cell emerges in a pathogen population in the presence of a drug.

Genetic barrier to resistance

The number of mutations required in a molecular target gene to confer a meaningful loss of susceptibility to a drug.

Irresistible drugs

In the context of antimalarial drug development, when all attempts to provoke resistance in vitro with a drug fail; that is, drugs with a low frequency of resistance and/or a high genetic barrier to resistance.

Partial resistance

(Also known as reduced parasite clearance). In the context of antimalarial drug resistance, particularly to artemisinin-based drugs, a delay in the clearance of malaria parasites due to a decrease of the parasite clearance rate after a properly administered treatment.

Phenotypic susceptibility testing association studies

Analyses of common mutations to determine their association with a specific phenotype or clinical outcome.

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Duffey, M., Shafer, R.W., Timm, J. et al. Combating antimicrobial resistance in malaria, HIV and tuberculosis. Nat Rev Drug Discov (2024). https://doi.org/10.1038/s41573-024-00933-4

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