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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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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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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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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DOI: https://doi.org/10.1038/s41589-020-00674-6
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