Article | Published:

Predictive compound accumulation rules yield a broad-spectrum antibiotic

Nature volume 545, pages 299304 (18 May 2017) | Download Citation

Abstract

Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Current understanding of the physicochemical properties that dictate small-molecule accumulation in Gram-negative bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and molecular weight are key factors. Here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Computational analysis of the results reveals major differences from the retrospective studies, namely that the small molecules that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-positive organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-negative pathogens. We anticipate that these findings will aid in the discovery and development of antibiotics against Gram-negative bacteria.

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Acknowledgements

We thank L. Li (Metabolomics Center, Roy J. Carver Biotechnology Center, UIUC) for LC–MS/MS analysis, L. Zechiedrich (Baylor College of Medicine) for the E. coli clinical isolates, C. Vanderpool (UIUC) for E. coli MG1655, and W. van der Donk (UIUC) for E. cloacae. We also thank K. Hull, S. Denmark, K. Morrison, R. Hicklin, H. Roth, B. Nakamura, A. Deets and A. Keyes for providing valuable compounds for the test set, and we thank M. Lambrecht for NMR expertise. This work was funded by the UIUC, including funds obtained through the Office of Technology Management Proof-of-Concept award. M.F.R. is a NSF predoctoral fellow. M.F.R., A.G., and R.L.S. are members of the NIH Chemistry-Biology Interface Training Grant (NRSA 1-T32-GM070421). A.P.R. is an NIH postdoctoral fellow. T.S. was supported by the Kao Corporation. Computer time was provided by the Texas Advanced Computing Center through Grant TG-CHE160050 funded by the NSF.

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Affiliations

  1. University of Illinois, Department of Chemistry and Institute for Genomic Biology, Urbana, Illinois 61801, USA

    • Michelle F. Richter
    • , Bryon S. Drown
    • , Andrew P. Riley
    • , Alfredo Garcia
    • , Tomohiro Shirai
    • , Riley L. Svec
    •  & Paul J. Hergenrother

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Contributions

P.J.H., M.F.R. and B.S.D. conceived the study. M.F.R. performed accumulation analyses. B.S.D. performed the computational analyses. M.F.R., B.S.D, A.P.R., A.G., T.S. and R.L.S. synthesized compounds in the test set. A.P.R. synthesized and tested DNM derivatives. P.J.H. supervised this research and wrote this manuscript with the assistance of M.F.R., B.S.D. and A.P.R.

Competing interests

The University of Illinois has filed patents on compounds related to this work.

Corresponding author

Correspondence to Paul J. Hergenrother.

Reviewer Information Nature thanks P. A. Clemons, S. Khalid, S. L. Schreiber, O. Verho, G. D. Wright and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature22308

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