Abstract
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.
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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.
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Acknowledgements
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 (http://scicore.unibas.ch/) 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).
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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.
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Extended data
Extended Data Fig. 1 Compound and Operon structures.
Shown are darobactin and putatively-related cyclophane RiPP products (dynobactin A, xenorceptide), BamA-targeting synthetic molecule (MRL-494), and theonellamide G which contains an unusual histidine Nε2 to alanine β-carbon linkage, similar to dynobactin histidine Nε2 to tyrosine β-carbon linkage.
Extended Data Fig. 2 Rapid identification of target metabolites.
Total ion chromatogram (TIC) and Escherichia coli MG1655 activity assay. Panels A-C correspond to C18 (A), PFP (B), and Phenyl (C) columns applied to a 0.1% (v/v) formic acid in water:acetonitrile gradient condition. Panels (D), (E), and (F) correspond to the same columns applied to a 0.1% (v/v) formic acid in water:methanol condition. Timeslice fractions which inhibit E. coli growth are indicated by highlighted boxes containing a ‘+’ symbol. (G) Summary of networked masses in antimicrobial ion exchange fraction. (H) Structure of biologically-active metabolites purified from Photorhabdus australis with GNPS network relationship to the dominant metabolite (dynobactin A).
Extended Data Fig. 3 CryoEM microED structure determination.
MicroED data collection and analysis of 19 independent crystals of dynobactin A yielded structure, further details are elaborated within Methods. (A) Bright-field TEM image of dynobactin crystals (Scale bar: 5 μm). (B) Electron diffraction pattern with resolution ring at 0.95 Å. (C) 2D crystal packing arrangements of dynobactin. The intramolecular hydrogen bonds are shown as dashed lines for the top two molecules. The crystallographic b axis is parallel to the vertical direction of the figure. (D) Dynobactin A shows flexible conformations. Left shows superimposition dynobactin A microED structure (straight) and the dynobactin A structure observed in co-crystal with target BamA (bent). Right panels depict individual structures side-by-side. Separation of the two macrocycle rings in dynobactin A allows for free rotation about 4 bonds, creating an approximate 90° kink in the dynobactin A structure.
Extended Data Fig. 4 Dynobactin Secondary Structural Confirmations.
Full NMR assignment available in Supplementary Table 4. (A) 1H NMR spectrum (900 MHz, D2O). (B) 13C NMR spectrum (225 MHz, D2O). (C) 2D NMR spectra recorded in D2O (top left HSQC, top right DQF-COSY, bottom left HMBC, bottom right ROESY). (D) Key 2D NMR correlations in D2O and DMSO-d6. (E) Retention times (tR, min) of FDLA derivatives from dynobactin A Marfey’s analysis.
Extended Data Fig. 5 Target identification and resistance mutations.
BamA crystal structure (green) with labeled resistance mutation sites identified in this paper: (A) front view of lateral gate and (B) view of the barrel lumen from the periplasmic side (underside). Sites identified which gave resistance to both compounds are labeled in blue, and a mutation site which gives resistance to only dynobactin A is labeled in magenta. (C) Table listing MICs for bacteria from the previously described darobactin-resistance evolution experiment15, the isolated dynobactin-resistant mutants from this study, and other E. coli strains with outer membrane deficiencies (that is porin or efflux knockouts).
Extended Data Fig. 6 Unique features of dynobactin A binding.
(A) Comparison of the co-crystal structure of BamA-β with bound darobactin A (PDB:7NRF) and with bound dynobactin A (this work). In the close-up panels, W810 is highlighted in red. (B) Comparison of the orientation of the compound relative to strand β16 of BamA in the two structures. The bulky C-terminal extension of dynobactin A displaces the C-terminus of BamA further into the barrel lumen, with residue W810 becoming flexibly disordered (C) Selected region of a 2D [15N,1H]-TROSY spectrum of BamA-β in LDAO micelles upon titration with dynobactin A. Tentative assignment for indole W810 is indicated. (D) Affinity measurements of darobactins and dynobactin A to BamA-β via Surface Plasmon Resonance, sensorgrams and the corresponding steady-state affinity plots show dynobactin A binds one order of magnitude tighter to BamA-barrel than the darobactins. (E) Efficacy of the compounds in inhibiting BAM-mediated folding in native outer membrane vesicles (OMVs) (data are presented as mean values ± SD, n = 2). Fitting of these data resulted in IC50 values of 30 ± 6 nM, 48 ± 8 nM, and 16 ± 2 nM for darobactin A, darobactin B and dynobactin A with a 95% confidence interval, respectively.
Extended Data Fig. 7 Cryo-EM and X-ray structure comparison of dynobactin A-bound BamA.
(A) X-ray crystal structure of BamA-β with bound dynobactin A at 2.5 Å resolution. Zoomed-in panels highlight specific residues involved in the interaction. (B) Hydrophobic interaction between V5 of dynobactin A to the side chains of F428 and I430 of BamA in the co-crystal structure. (C) Interaction between W1 of dynobactin A and BamA. (D) Superimposition of the X-ray and cryo-EM structures (β-strand 1 only). The comparison shows a high degree of similarity in the conformation of dynobactin A between the cryo-EM and X-ray structure.
Extended Data Fig. 8 Solution NMR spectroscopy of BamA-β interacting with dynobactin A.
(A) 2D [15N,1H]-TROSY spectra of apo BamA-β in LDAO micelles (green) overlaid with BamA-β with 1.0 eq of dynobactin A (magenta). Zoomed-in panels show selected resonances. Tentatively assigned W810 is indicated with a frame on the spectrum. (B) 2D [15N,1H]-TROSY spectra of BamA-β in a titration experiment with increasing concentration of dynobactin A, as indicated, from black to red. (C) NMR spectrum of mutant W810F to confirm the assignment of W810.
Extended Data Fig. 9 Time-lapse microscopy of E. coli undergoing dynobactin A treatment.
E. coli MG1655 cells were spotted onto a 1.5% agarose pad containing dynobactin A (8x MIC), the membrane stain FM4-64 10 μg mL-1 (false-colored in magenta), and membrane permeabilization stain Sytox Green 0.5 μM (false-colored in green). Cells were incubated at 37 °C in a thermostatic chamber and imaged every 15 minutes under the microscope. The panels and selected time points were chosen to best represent the population of E. coli MG1655 undergoing dynobactin A treatment. White arrows indicate representative examples of membrane blebbing; orange arrows indicate examples of swelling or cell lysis. Scale bars, 5 μm. This experiment is representative of two biologically-independent experiments performed, each showing similar results.
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Miller, R.D., Iinishi, A., Modaresi, S.M. et al. Computational identification of a systemic antibiotic for Gram-negative bacteria. Nat Microbiol 7, 1661–1672 (2022). https://doi.org/10.1038/s41564-022-01227-4
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DOI: https://doi.org/10.1038/s41564-022-01227-4
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