Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Antibiotic Resistance Threats in the United States 2019 (Centers for Disease Control and Prevention, 2019); https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf

  2. Antimicrobial Resistance: Global Report on Surveillance 2014 (World Health Organization, 2014); http://www.who.int/drugresistance/documents/surveillancereport/en/

  3. A Scientific Roadmap for Antibiotic Discovery (The Pew Charitable Trusts, 2016); https://www.pewtrusts.org/en/research-and-analysis/reports/2016/05/a-scientific-roadmap-for-antibiotic-discovery

  4. Rice, L. B. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J. Infect. Dis. 197, 1079–1081 (2008).

    PubMed  Google Scholar 

  5. De Oliveira, D. M. P. et al. Antimicrobial resistance in ESKAPE pathogens. Clin. Microbiol. Rev. 33, e00181 (2020).

    PubMed  Google Scholar 

  6. Tracking the Global Pipeline of Antibiotics in Development, April 2020 (The Pew Charitable Trusts, 2020); https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2020/04/tracking-the-global-pipeline-of-antibiotics-in-development

  7. Nikaido, H. Molecular basis of bacterial outer membrane permeability revisited. Microbiol. Mol. Biol. Rev. 67, 593–656 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Zgurskaya, H. I., Lopez, C. A. & Gnanakaran, S. Permeability barrier of Gram-negative cell envelopes and approaches to bypass it. ACS Infect. Dis. 1, 512–522 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Silver, L. L. A Gestalt approach to Gram-negative entry. Bioorg. Med. Chem. 24, 6379–6389 (2016).

    CAS  PubMed  Google Scholar 

  10. Masi, M., Refregiers, M., Pos, K. M. & Pages, J.-M. Mechanisms of envelope permeability and antibiotic influx and efflux in Gram-negative bacteria. Nat. Microbiol. 2, 17001 (2017).

    CAS  PubMed  Google Scholar 

  11. Tommasi, R., Iyer, R. & Miller, A. A. Antibacterial drug discovery: some assembly required. ACS Infect. Dis. 4, 686–695 (2018).

    CAS  PubMed  Google Scholar 

  12. Zgurskaya, H. I. & Rybenkov, V. V. Permeability barriers of Gram-negative pathogens. Ann. N. Y. Acad. Sci. 1459, 5–18 (2020).

    PubMed  Google Scholar 

  13. Saha, P., Sikdar, S., Krishnamoorthy, G., Zgurskaya, H. I. & Rybenkov, V. V. Drug permeation against efflux by two transporters. ACS Infect. Dis. 6, 747–758 (2020).

    CAS  PubMed  Google Scholar 

  14. Westfall, D. A. et al. Bifurcation kinetics of drug uptake by Gram-negative bacteria. PLoS ONE 12, e0184671 (2017). A kinetic model that accurately describes small-molecule permeation of the Gram-negative envelope was developed. The model-predicted complex, nonlinear patterns dependent on concentration and time that were validated experimentally.

    PubMed  PubMed Central  Google Scholar 

  15. Krishnamoorthy, G. et al. Synergy between active efflux and outer membrane diffusion defines rules of antibiotic permeation into Gram-negative bacteria. mBio 8, e01172 (2017). Analysis of the activity of antibiotics in four-strain sets of wild-type, hyperporinated, efflux-deficient, and doubly-compromised A. baumannii, P. aeruginosa, and Burkholderia spp. revealed a synergistic relationship between efflux and the permeability barrier in protecting these bacteria from structurally diverse antibiotics.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discovery 6, 29–40 (2007).

    CAS  PubMed  Google Scholar 

  17. Tommasi, R., Brown, D. G., Walkup, G. K., Manchester, J. I. & Miller, A. A. ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discovery 14, 529–542 (2015).

    CAS  PubMed  Google Scholar 

  18. Lewis, K. Antibiotics: Recover the lost art of drug discovery. Nature 485, 439–440 (2012).

    CAS  PubMed  Google Scholar 

  19. Kamio, Y. & Nikaido, H. Outer membrane of Salmonella typhimurium: accessibility of phospholipid head groups to phospholipase C and cyanogen bromide activated dextran in the external medium. Biochemistry 15, 2561–2570 (1976).

    CAS  PubMed  Google Scholar 

  20. Raetz, C. R. & Whitfield, C. Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635–700 (2002).

    CAS  PubMed  Google Scholar 

  21. Henderson, J. C. et al. The power of asymmetry: architecture and assembly of the Gram-negative outer membrane lipid bilayer. Annu. Rev. Microbiol. 70, 255–278 (2016).

    CAS  PubMed  Google Scholar 

  22. Vergalli, J. et al. Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria. Nat. Rev. Microbiol. 18, 164–176 (2020).

    CAS  PubMed  Google Scholar 

  23. Zgurskaya, H. I., Rybenkov, V. V., Krishnamoorthy, G. & Leus, I. V. Trans-envelope multidrug efflux pumps of Gram-negative bacteria and their synergism with the outer membrane barrier. Res. Microbiol. 169, 351–356 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Poirel, L., Jayol, A. & Nordmann, P. Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin. Microbiol. Rev. 30, 557–596 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Pagnout, C. et al. Pleiotropic effects of rfa-gene mutations on Escherichia coli envelope properties. Sci. Rep. 9, 9696 (2019).

    PubMed  PubMed Central  Google Scholar 

  26. Krishnamoorthy, G. et al. Breaking the permeability barrier of Escherichia coli by controlled hyperporination of the outer membrane. Antimicrob. Agents Chemother. 60, 7372–7381 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Leus, I. V. et al. Substrate specificities and efflux efficiencies of RND efflux pumps of Acinetobacter baumannii. J. Bacteriol. 200, e00049 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Krishnamoorthy, G. et al. Efflux pumps of Burkholderia thailandensis control the permeability barrier of the outer membrane. Antimicrob. Agents Chemother. 63, e00956 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Sohlenkamp, C. & Geiger, O. Bacterial membrane lipids: diversity in structures and pathways. FEMS Microbiol. Rev. 40, 133–159 (2016).

    CAS  PubMed  Google Scholar 

  30. Richter, M. F. & Hergenrother, P. J. The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics. Ann. N. Y. Acad. Sci. 1435, 18–38 (2019).

    CAS  PubMed  Google Scholar 

  31. Richter, M. F. et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545, 299–304 (2017). Screening of a library of 100 diverse, natural-product-derived compounds for compound accumulation in E. coli identified a primary amine, amphiphilic moment, low globularity, and rigidity as factors associated with accumulation, enabling design of a Gram-negative-active analogue of a Gram-positive-restricted antibiotic.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Parker, E. N. et al. Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens. Nat. Microbiol. 5, 67–75 (2020).

    CAS  PubMed  Google Scholar 

  33. Motika, S. E. et al. Gram-negative antibiotic active through inhibition of an essential riboswitch. J. Am. Chem. Soc. 142, 10856–10862 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Isabella, V. M. et al. Toward the rational design of carbapenem uptake in Pseudomonas aeruginosa. Chem. Biol. 22, 535–547 (2015).

    CAS  PubMed  Google Scholar 

  35. Li, Y. et al. First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors. Bioorg. Med. Chem. Lett. 29, 1836–1841 (2019).

    PubMed  PubMed Central  Google Scholar 

  36. Green, A. T. et al. Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold. Biochim. Biophys. Acta Gen. Subj. 1864, 129546 (2020).

    CAS  PubMed  Google Scholar 

  37. Nestorovich, E. M., Danelon, C., Winterhalter, M. & Bezrukov, S. M. Designed to penetrate: time-resolved interaction of single antibiotic molecules with bacterial pores. Proc. Natl Acad. Sci. USA 99, 9789–9794 (2002).

    CAS  PubMed  Google Scholar 

  38. Wang, J., Terrasse, R., Bafna, J. A., Benier, L. & Winterhalter, M. Electrophysiological characterization of transport across outer-membrane channels from Gram-negative bacteria in presence of lipopolysaccharides. Angew. Chem. Int. Ed. 59, 8517–8521 (2020).

    CAS  Google Scholar 

  39. Acosta-Gutierrez, S. et al. Getting drugs into Gram-negative bacteria: rational rules for permeation through general porins. ACS Infect. Dis. 4, 1487–1498 (2018).

    CAS  PubMed  Google Scholar 

  40. Cooper, S. J. et al. Molecular properties that define the activities of antibiotics in Escherichia coli and Pseudomonas aeruginosa. ACS Infect. Dis. 4, 1223–1234 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Iyer, R. et al. Whole-cell-based assay to evaluate structure permeation relationships for carbapenem passage through the Pseudomonas aeruginosa porin OprD. ACS Infect. Dis. 3, 310–319 (2017).

    CAS  PubMed  Google Scholar 

  42. Nikaido, H. Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264, 382–388 (1994).

    CAS  PubMed  Google Scholar 

  43. Iyer, R. et al. Evaluating LC-MS/MS to measure accumulation of compounds within bacteria. ACS Infect. Dis. 4, 1336–1345 (2018). Screening of a library of >100 DNA ligase inhibitors for compound accumulation in E. coli showed poor correlation between overall bacteria-associated compound levels and antibacterial activity in compounds with matched biochemical activities, highlighting the importance of subcellular localization.

    CAS  PubMed  Google Scholar 

  44. Widya, M. et al. Development and optimization of a higher-throughput bacterial compound accumulation assay. ACS Infect. Dis. 5, 394–405 (2019).

    CAS  PubMed  Google Scholar 

  45. O’Shea, R. & Moser, H. E. Physicochemical properties of antibacterial compounds: implications for drug discovery. J. Med. Chem. 51, 2871–2878 (2008).

    PubMed  Google Scholar 

  46. Davis, T. D., Gerry, C. J. & Tan, D. S. General platform for systematic quantitative evaluation of small-molecule permeability in bacteria. ACS Chem. Biol. 9, 2535–2544 (2014). A platform for prospective, activity-independent analysis of compound accumulation in bacteria was developed. Analysis of a panel of acyl sulfamoyladenosines identified physicochemical properties that correlate with accumulation, enabling the design of analogues with increased accumulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Brown, D. G., May-Dracka, T. L., Gagnon, M. M. & Tommasi, R. Trends and exceptions of physical properties on antibacterial activity for Gram-positive and Gram-negative pathogens. J. Med. Chem. 57, 10144–10161 (2014).

    CAS  PubMed  Google Scholar 

  48. Novick, R. P. Microiodometric assay for penicillinase. Biochem. J. 83, 236–240 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Zimmermann, W. & Rosselet, A. Function of the outer membrane of Escherichia coli as a permeability barrier to beta-lactam antibiotics. Antimicrob. Agents Chemother. 12, 368–372 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Murakami, K. & Yoshida, T. Penetration of cephalosporins and corresponding 1-oxacephalosporins through the outer layer of Gram-negative bacteria and its contribution to antibacterial activity. Antimicrob. Agents Chemother. 21, 254–258 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Nikaido, H., Rosenberg, E. Y. & Foulds, J. Porin channels in Escherichia coli: studies with beta-lactams in intact cells. J. Bacteriol. 153, 232–240 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Yoshimura, F. & Nikaido, H. Diffusion of β-lactam antibiotics through the porin channels of Escherichia coli K-12. Antimicrob. Agents Chemother. 27, 84–92 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chopra, I. & Hacker, K. Uptake of minocycline by Escherichia coli. J. Antimicrob. Chemother. 29, 19–25 (1992).

    CAS  PubMed  Google Scholar 

  54. Diver, J. M., Piddock, L. J. V. & Wise, R. The accumulation of five quinolone antibacterial agents by Escherichia coli. J. Antimicrob. Chemother. 25, 319–333 (1990).

    CAS  PubMed  Google Scholar 

  55. Mortimer, P. G. S. & Piddock, L. J. V. A comparison of methods used for measuring the accumulation of quinolones by Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. J. Antimicrob. Chemother. 28, 639–653 (1991).

    CAS  PubMed  Google Scholar 

  56. Bazile, S., Moreau, N., Bouzard, D. & Essiz, M. Relationship among antibacterial activity, inhibition of DNA gyrase, and intracellular accumulation of 11 fluoroquinolones. Antimicrob. Agents Chemother. 36, 2622–2627 (1992). This is a seminal early study demonstrating the integration of compound accumulation levels with biochemical inhibitory activity to predict antibacterial activity in E. coli and P. aeruginosa.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. McCaffrey, C., Bertasso, A., Pace, J. & Georgopapadakou, N. H. Quinolone accumulation in Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Antimicrob. Agents Chemother. 36, 1601–1605 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Asuquo, A. E. & Piddock, L. J. Accumulation and killing kinetics of fifteen quinolones for Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. J. Antimicrob. Chemother. 31, 865–880 (1993).

    CAS  PubMed  Google Scholar 

  59. Piddock, L. J. V., Jin, Y. F. & Griggs, D. J. Effect of hydrophobicity and molecular mass on the accumulation of fluoroquinolones by Staphylococcus aureus. J. Antimicrob. Chemother. 47, 261–270 (2001).

    CAS  PubMed  Google Scholar 

  60. Mortimer, P. G. S. & Piddock, L. J. V. The accumulation of five antibacterial agents in porin-deficient mutants of Escherichia coli. J. Antimicrob. Chemother. 32, 195–213 (1993).

    CAS  PubMed  Google Scholar 

  61. Piddock, L. J. V., Jin, Y. F., Ricci, V. & Asuquo, A. E. Quinolone accumulation by Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. J. Antimicrob. Chemother. 43, 61–70 (1999).

    CAS  PubMed  Google Scholar 

  62. Cai, H., Rose, K., Liang, L.-H., Dunham, S. & Stover, C. Development of a liquid chromatography/mass spectrometry-based drug accumulation assay in Pseudomonas aeruginosa. Anal. Biochem. 385, 321–325 (2009).

    CAS  PubMed  Google Scholar 

  63. Ferreras, J. A., Ryu, J.-S., Di Lello, F., Tan, D. S. & Quadri, L. E. N. Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat. Chem. Biol. 1, 29–32 (2005).

    CAS  PubMed  Google Scholar 

  64. Huigens, R. W. et al. A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nat. Chem. 5, 195–202 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. O’Connor, C. J., Beckmann, H. S. G. & Spring, D. R. Diversity-oriented synthesis: producing chemical tools for dissecting biology. Chem. Soc. Rev. 41, 4444–4456 (2012).

    Google Scholar 

  66. Gerry, C. J. & Schreiber, S. L. Recent achievements and current trajectories of diversity-oriented synthesis. Curr. Opin. Chem. Biol. 56, 1–9 (2020).

    CAS  PubMed  Google Scholar 

  67. Prochnow, H. et al. Subcellular quantification of uptake in Gram-negative bacteria. Anal. Chem. 91, 1863–1872 (2019).

    CAS  PubMed  Google Scholar 

  68. Zhou, Y. et al. Thinking outside the “bug”: a unique assay to measure intracellular drug penetration in Gram-negative bacteria. Anal. Chem. 87, 3579–3584 (2015).

    CAS  PubMed  Google Scholar 

  69. Blair, J. M. A. & Piddock, L. J. V. How to measure export via bacterial multidrug resistance efflux pumps. mBio 7, e00840 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Stone, M. R. L., Butler, M. S., Phetsang, W., Cooper, M. A. & Blaskovich, M. A. T. Fluorescent antibiotics: new research tools to fight antibiotic resistance. Trends Biotechnol. 36, 523–536 (2018).

    CAS  PubMed  Google Scholar 

  71. Tanner, L., Denti, P., Wiesner, L. & Warner, D. F. Drug permeation and metabolism in Mycobacterium tuberculosis: prioritising local exposure as essential criterion in new TB drug development. IUBMB Life 70, 926–937 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kaščáková, S., Maigre, L., Chevalier, J., Réfrégiers, M. & Pagès, J.-M. Antibiotic transport in resistant bacteria: synchrotron UV fluorescence microscopy to determine antibiotic accumulation with single cell resolution. PLoS ONE 7, e38624 (2012).

    PubMed  PubMed Central  Google Scholar 

  73. Vergalli, J. et al. Spectrofluorimetric quantification of antibiotic drug concentration in bacterial cells for the characterization of translocation across bacterial membranes. Nat. Protoc. 13, 1348–1361 (2018).

    CAS  PubMed  Google Scholar 

  74. Paixão, L. et al. Fluorometric determination of ethidium bromide efflux kinetics in Escherichia coli. J. Biol. Eng. 3, 18 (2009).

    PubMed  PubMed Central  Google Scholar 

  75. Whittle, E. E. et al. Flow cytometric analysis of efflux by dye accumulation. Front. Microbiol. 10, 2319 (2019).

    PubMed  PubMed Central  Google Scholar 

  76. Prideaux, B. et al. High-sensitivity MALDI-MRM-MS imaging of moxifloxacin distribution in tuberculosis-infected rabbit lungs and granulomatous lesions. Anal. Chem. 83, 2112–2118 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Prideaux, B. et al. Mass spectrometry imaging of levofloxacin distribution in TB-infected pulmonary lesions by MALDI-MSI and continuous liquid microjunction surface sampling. Int. J. Mass Spectrom. 377, 699–708 (2015).

    CAS  PubMed  Google Scholar 

  78. Van Pelt, C. K. et al. A fully automated nanoelectrospray tandem mass spectrometric method for analysis of Caco-2 samples. Rapid Commun. Mass Spectrom. 17, 1573–1578 (2003).

    PubMed  Google Scholar 

  79. Chen, C. Y., Lam, B. L. & Bhattacharya, S. K. Mass spectrometric analyses of phospholipids in the S334ter-3 rat model of retinal degeneration. Mol. Vis. 20, 1605–1611 (2014).

    PubMed  PubMed Central  Google Scholar 

  80. Yan, C. et al. Real-time screening of biocatalysts in live bacterial colonies. J. Am. Chem. Soc. 139, 1408–1411 (2017).

    CAS  PubMed  Google Scholar 

  81. Wleklinski, M. et al. High throughput reaction screening using desorption electrospray ionization mass spectrometry. Chem. Sci. 9, 1647–1653 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Sinclair, I. et al. Novel acoustic loading of a mass spectrometer: toward next-generation high-throughput MS screening. J. Lab. Autom. 21, 19–26 (2016).

    PubMed  Google Scholar 

  83. Heidari Torkabadi, H. et al. Following drug uptake and reactions inside Escherichia coli cells by Raman microspectroscopy. Biochemistry 53, 4113–4121 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Stratford, J. P. et al. Electrically induced bacterial membrane-potential dynamics correspond to cellular proliferation capacity. Proc. Natl Acad. Sci. USA 116, 9552–9557 (2019).

    CAS  PubMed  Google Scholar 

  85. Cama, J., Henney, A. M. & Winterhalter, M. Breaching the barrier: quantifying antibiotic permeability across Gram-negative bacterial membranes. J. Mol. Biol. 431, 3531–3546 (2019).

    CAS  PubMed  Google Scholar 

  86. Kuhn, P., Eyer, K., Allner, S., Lombardi, D. & Dittrich, P. S. A microfluidic vesicle screening platform: monitoring the lipid membrane permeability of tetracyclines. Anal. Chem. 83, 8877–8885 (2011).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding authors

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

Ethics declarations

Competing interests

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing