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Computational identification of a systemic antibiotic for Gram-negative bacteria

Miller, Ryan D. and Iinishi, Akira and Modaresi, Seyed Majed and Yoo, Byung-Kuk and Curtis, Thomas D. and Lariviere, Patrick J. and Liang, Libang and Son, Sangkeun and Nicolau, Samantha and Bargabos, Rachel and Morrissette, Madeleine and Gates, Michael F. and Pitt, Norman and Jakob, Roman P. and Rath, Parthasarathi and Maier, Timm and Malyutin, Andrey G. and Kaiser, Jens T. and Niles, Samantha and Karavas, Blake and Ghiglieri, Meghan and Bowman, Sarah E. J. and Rees, Douglas C. and Hiller, Sebastian and Lewis, Kim (2022) Computational identification of a systemic antibiotic for Gram-negative bacteria. Nature Microbiology, 7 (10). pp. 1661-1672. ISSN 2058-5276. doi:10.1038/s41564-022-01227-4.

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Discovery of antibiotics acting against Gram-negative species is uniquely challenging due to their restrictive penetration barrier. BamA, which inserts proteins into the outer membrane, is an attractive target due to its surface location. Darobactins produced by Photorhabdus, a nematode gut microbiome symbiont, target BamA. We reasoned that a computational search for genes only distantly related to the darobactin operon may lead to novel compounds. Following this clue, we identified dynobactin A, a novel peptide antibiotic from Photorhabdus australis containing two unlinked rings. Dynobactin is structurally unrelated to darobactins, but also targets BamA. Based on a BamA-dynobactin co-crystal structure and a BAM-complex-dynobactin cryo-EM structure, we show that dynobactin binds to the BamA lateral gate, uniquely protruding into its β-barrel lumen. Dynobactin showed efficacy in a mouse systemic Escherichia coli infection. This study demonstrates the utility of computational approaches to antibiotic discovery and suggests that dynobactin is a promising lead for drug development.

Item Type:Article
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URLURL TypeDescription ReadCube access
Miller, Ryan D.0000-0002-0723-8658
Modaresi, Seyed Majed0000-0001-9747-9748
Yoo, Byung-Kuk0000-0002-2610-6685
Lariviere, Patrick J.0000-0002-8427-3879
Maier, Timm0000-0002-7459-1363
Malyutin, Andrey G.0000-0003-1716-5437
Kaiser, Jens T.0000-0002-5948-5212
Karavas, Blake0000-0002-6258-414X
Bowman, Sarah E. J.0000-0002-7426-7328
Rees, Douglas C.0000-0003-4073-1185
Hiller, Sebastian0000-0002-6709-4684
Lewis, Kim0000-0002-1335-9982
Additional Information:Photorhabdus australis isolates were kindly shared by N. Waterfield at the University of Warwick as well as by A. Thanwisai from Naresuan University. Crystallization screening at the National Crystallization Center at HWI was supported through NIH grant R24GM141256. B.-K.Y. thanks L. M. Henling for fruitful discussions. The microED data were collected at the Caltech cryo-EM facility. We thank S. Chen for assistance and the Beckman Institute for their generous support of the cryo-EM facility and the Molecular Observatory at Caltech; the Korea Basic Science Institute, Ochang, Korea, for providing NMR (900 MHz) data; the staff of beamlines X06DA and X06SA at the Paul Scherrer Institute, Villigen, Switzerland, for support with crystallographic data collection; and the BioEM lab of the University of Basel for support with cryo-EM data acquisition. Calculations were performed at sciCORE ( scientific computing core facility at the University of Basel. This project was supported by the National Institutes of Health grant P01 AI118687 (K.L.), the Swiss National Science Foundation grants 177084 (T.M.) and 187170 (S.H.), and the National Center of Competence in Research AntiResist (180541). These authors contributed equally: Ryan D. Miller, Akira Iinishi, Seyed Majed Modaresi, Byung-Kuk Yoo. Contributions. K.L. conceptualized the project; R.D.M., A.I., S.M.M., B.-K.Y., D.C.R., S.H. and K.L. developed the methodology; R.D.M., A.I., S.M.M., B.K.-Y., T.D.C., P.J.L., L.L., S.S., S.N., R.B., M.M., M.F.G., N.P., R.P.J., P.R., T.M., A.G.M., J.T.K., S.N., B.K., M.G., S.B. conducted the investigations; R.D.M., S.M.M., S.H. and K.L. wrote the manuscript; D.C.R., S.H. and K.L. acquired funding; and D.C.R., S.H. and K.L. supervised the project. Data availability. Data supporting the findings of this study are available within the paper and its Supplementary Information, and have been submitted to publicly available databases. Crystal structures are available through PDB: microED dynobactin A structure (7T3H), BamA:dynobactin A X-ray co-crystal (7R1V), BAM complex:dynobactin A cryo-EM (7R1W, EMD-14242). Any other data or datasets from the current study are available upon reasonable request to the corresponding authors. The authors declare no competing interests. Peer review information. Nature Microbiology thanks Paul Hergenrother and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Funding AgencyGrant Number
NIHP01 AI118687
Swiss National Science Foundation (SNSF)177084
Swiss National Science Foundation (SNSF)187170
Swiss National Science Foundation (SNSF)180541
Issue or Number:10
Record Number:CaltechAUTHORS:20221006-438893200.4
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ID Code:117279
Deposited By: Research Services Depository
Deposited On:12 Oct 2022 23:57
Last Modified:12 Oct 2022 23:57

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