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The challenge of new drug discovery for tuberculosis

Abstract

Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients.

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Figure 1: Stages of M. tuberculosis infection.
Figure 2: A bull’s-eye representation of the current clinical pipeline for TB.
Figure 3: Screening for mycobacterial respiratory pathway inhibitors.
Figure 4: Remodelling the existing antibacterial drug classes.
Figure 5: Two-dimensional representation of chemical space of the anti-TB drugs.
Figure 6: Representative underexplored and new chemical scaffolds.

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Acknowledgements

We thank our colleagues K. Simmen, N. Austin, V. Sinha, H. Van Vlijmen and M. Macleigh for critical reading and providing valuable scientific input for this manuscript. We would also like to thank B. Challis for reviewing this manuscript, S. Mostmans from the Business Intelligence Group for providing TB pipeline updates, and E. Huybrechts for her help with preparing the figures.

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Contributions

A.K. wrote the synopsis, conceptualized different topics within the review, wrote and contributed to all sections of the review; coordinated and discussed the content with other co-authors. E.A. did the principal component analysis work on TB drugs, N.L. contributed to the section on animal models, J.G. did the chemistry part of the review including chemical structures and K.A. contributed to different sections of the review with a major focus on TB clinical development.

Corresponding author

Correspondence to Anil Koul.

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Competing interests

The authors are employees of Johnson and Johnson and are currently involved in the development of new TB drug TMC207.

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Koul, A., Arnoult, E., Lounis, N. et al. The challenge of new drug discovery for tuberculosis. Nature 469, 483–490 (2011). https://doi.org/10.1038/nature09657

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