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Defining new chemical space for drug penetration into Gram-negative bacteria

Nature Chemical Biology volume 16, pages 1293–1302 (2020)Cite this article

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Abstract

We live in the era of antibiotic resistance, and this problem will progressively worsen if no new solutions emerge. In particular, Gram-negative pathogens present both biological and chemical challenges that hinder the discovery of new antibacterial drugs. First, these bacteria are protected from a variety of structurally diverse drugs by a low-permeability barrier composed of two membranes with distinct permeability properties, in addition to active drug efflux, making this cell envelope impermeable to most compounds. Second, chemical libraries currently used in drug discovery contain few compounds that can penetrate Gram-negative bacteria. As a result of these challenges, intensive screening campaigns have led to few successes, highlighting the need for new approaches to identify regions of chemical space that are specifically relevant to antibacterial drug discovery. Herein we provide an overview of emerging insights into this problem and outline a general approach to addressing it using prospective analysis of chemical libraries for the ability of compounds to accumulate in Gram-negative bacteria. The overall goal is to develop robust cheminformatic tools to predict Gram-negative permeation and efflux, which can then be used to guide medicinal chemistry campaigns and the design of antibacterial discovery libraries.

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Fig. 1: The Gram-negative cell envelope and pathways of drug fluxes across it.
Fig. 2: Comprehensive approach to developing cheminformatic tools to predict Gram-negative bacterial compound accumulation.

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Acknowledgements

We thank A. Duerfeldt and V. Rybenkov (University of Oklahoma); C. Balibar, D. McLaren, B. Sherborne, B. Squadroni, M. Tudor, and S. Walker (Merck Research Labs); H. Voss (Weill Cornell Medicine); and the entire SPEAR-GN team for helpful discussions. Financial support from the National Institutes of Health (R01 AI136795 to D.S.T. and H.I.Z.; R01 GM100477 and R01 AI118224 to D.S.T.; R01 AI136799 to H.I.Z.; and MSK CCSG P30 CA008748 to C. B. Thompson) is gratefully acknowledged.

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  1. These authors contributed equally: Shibin Zhao, Justyna W. Adamiak.

Authors and Affiliations

  1. Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Shibin Zhao & Derek S. Tan

  2. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, USA

    Justyna W. Adamiak, Vincent Bonifay, Jitender Mehla & Helen I. Zgurskaya

  3. Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Derek S. Tan

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Contributions

All authors contributed to the writing and editing of this manuscript. J.W.A. and H.I.Z. contributed Fig. 1. D.S.T. contributed Fig. 2. S.Z. and D.S.T. contributed Table 1. J.W.A., V.B., and H.I.Z. contributed Table 2.

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Correspondence to Helen I. Zgurskaya or Derek S. Tan.

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Merck is a collaborating institution on the SPEAR-GN project and has provided in-kind support to the labs of D.S.T. and H.I.Z. D.S.T. serves on the External Advisory Board of the Institute for Research in Biomedicine, Barcelona; is a shareholder and has been a paid consultant and speaker for Merck; and has been a paid consultant or speaker for Eli Lilly, Elsevier, Emerson Collective, and Venenum Biosciences. H.I.Z. has been a paid speaker for Genentech and Novartis Research Institutes.

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Zhao, S., Adamiak, J.W., Bonifay, V. et al. Defining new chemical space for drug penetration into Gram-negative bacteria. Nat Chem Biol 16, 1293–1302 (2020). https://doi.org/10.1038/s41589-020-00674-6

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