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Innovation in the preclinical antibiotic pipeline

Nature Reviews Drug Discovery volume 16, pages 744–745 (2017)Cite this article

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More than 50 small-molecule preclinical projects among the CARB-X submissions focused on at least one of the critical priority pathogens on the WHO global priority list that was recently published to guide antibiotic R&D, which are all extensively drug-resistant Gram-negative bacteria. The small molecules being investigated by these projects belong to new chemical and/or functional classes with no anticipated cross-resistance to existing classes (Fig. 1a). These projects exhibit considerable diversity, with several clusters (Fig. 1b) as well as a large group of projects classified as 'other'. The largest cluster are membrane-targeting agents, including compounds modelled on natural antimicrobial peptides. There is also a substantial cluster of agents that inhibit LpxC, the enzyme responsible for the first committed step in the biosynthesis of lipid A — a key component of the outer membrane of Gram-negative bacteria.

Another prominent trend is the strong focus on biologics, including antibodies, antibacterial vaccines, antibody–drug conjugates and other large molecules (Fig. 1a). Such pathogen-specific strategies are usually intended for pre-emptive use. Some of these biologics target bacterial virulence factors, and it is notable that there are also multiple small-molecule projects targeting bacterial virulence mechanisms in other ways.Phage-related products are also prominent (Fig. 1a). In contrast to earlier years, there are fewer projects with phage cocktails, and more genetic engineering efforts, using phages for delivery and phage products such as endolysins as starting points.

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Figure 1: Analysis of CARB-X applications.

Acknowledgements

U.T, M.S. and C.Å. were partly supported by the Innovative Medicines Initiative Joint Undertaking DRIVE-AB grant number 115583; M.S. and C.Å. are partly funded by the Norwegian Research Council (grant number 234608); K.O. is supported by the Cooperative Agreement Number 6 IDSEP160030-02-01from the Biomedical Advanced Research and Development Authority (BARDA) and by an award from the Wellcome Trust. CARB-X is also supported by the National Institute of Allergy and Infectious Diseases. This article is solely the responsibility of the authors and does not necessarily represent the official views of The Assistant Secretary for Preparedness and Response, the National Institutes of Health, the Wellcome Trust, DRIVE-AB or the Innovative Medicines Initiative.

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Authors and Affiliations

  1. Center for Anti-Infective Agents, Eckpergasse 13, Vienna, 1180, Austria

    Ursula Theuretzbacher

  2. Norwegian Institute of Public Health, PO Box 4404, Nydalen, Oslo, N-0403, Norway

    Miloje Savic & Christine Årdal

  3. Boston University School of Law, Boston, 02215, Massachusetts, USA

    Kevin Outterson

  4. CARB-X,

    Kevin Outterson

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  1. Ursula Theuretzbacher
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  2. Miloje Savic
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Correspondence to Ursula Theuretzbacher.

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Theuretzbacher, U., Savic, M., Årdal, C. et al. Innovation in the preclinical antibiotic pipeline. Nat Rev Drug Discov 16, 744–745 (2017). https://doi.org/10.1038/nrd.2017.195

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