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Human commensals producing a novel antibiotic impair pathogen colonization

A Corrigendum to this article was published on 14 September 2016

Abstract

The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.

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Figure 1: Lugdunin production by wild-type S. lugdunensis and isogenic mutants.
Figure 2: Gene cluster, proposed biosynthesis pathway and chemical structure of lugdunin.
Figure 3: Lugdunin has bactericidal activity, a low risk for resistance and efficacy in a mouse skin infection model.
Figure 4: Lugdunin-producing wild-type S. lugdunensis IVK28 restricts the growth of S. aureus in vitro and in vivo in cotton rats.

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Acknowledgements

We thank V. Winstel for technical assistance and A. Bobic, S. Heilbronner, W. Hoffmann, A. Jorge, D. Kretschmer, A. Kulik, M. Nega, E. Stegmann, V. Winstel, T. Weber, and W. Wohlleben for assistance and helpful discussions. Thanks to Bruker Daltonics for selected initial high-resolution mass spectrometry analysis and to T. Paululat for NMR experiments. This work was financed by German Research Council grants GRK1708 to S.G. and A.P.; TRR156, Schi510/8-1, and PE805/5-1 to B.S. and A.P.; TRR34 to C.W. and A.P; and SFB766 to C.W., H.B.-O., S.G., and A.P.; and by the German Center for Infection Research (DZIF) to C.W., A.P., B.K., M.W., and H.B.-O.

Author information

Authors and Affiliations

Authors

Contributions

A.Z. isolated lugdunin, designed experiments and investigated the biological activities of lugdunin. M.C.K. purified lugdunin, designed experiments and determined the structure of lugdunin. D.J. identified IVK28 and performed transposon mutagenesis. A.B. designed and performed precursor incorporation studies. C.L. designed the human colonization study and analysed data. M.B., A.Z., C.S. and C.W. performed animal experiments, and M.W. and C.W. analysed data and performed statistical analysis. M.M. provided patient samples and supported MALDI-TOF analysis. N.A.S. and H.K. established total chemical synthesis of lugdunin. B.K. isolated lugdunin, analysed operon structure and performed bioinformatic analyses, A.Z., M.C.K., B.S., H.B.-O., S.G., A.P. and B.K. designed the study, analysed results, and wrote the paper.

Corresponding author

Correspondence to Andreas Peschel.

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Competing interests

Tuebingen University has filed a provisional patent application that covers the compound lugdunin and derivatives thereof, as well as the application of lugdunin- producing bacteria for the prevention of bacterial infections (European patent application number EP 15 160 285.1).

Additional information

Reviewer Information Nature thanks G. Challis, M. Gilmore and K. Lewis for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 Gene cluster of lugdunin and generation of S. lugdunensis IVK28-Xyl.

a, The lugdunin genes are located on a 30-kbp operon. lugA–D encode the four NRPS, which are preceded by the putative regulator gene lugR. Encoded upstream are putative ABC transporter genes (lugEH) and genes for proteins with no described function (lugI and lugJ). A type-II thioesterase, that functions as a repair enzyme for stalled PCP domains, is encoded between lugC and lugD. The 4’-phosphopantetheinyl transferase LugZ converts inactive PCPs (apo-PCP) into the active holo-form by attachment of the 4’-phosphopantetheine cofactor. Encoded downstream is a putative monooxygenase (lugM). The transposon insertion site of Tn917, generating the lugdunin-deficient mutant IVK28 M1, is indicated by a red arrow. b, The xylose-inducible lugdunin producer strain S. lugdunensis IVK28-xyl was generated by replacement of the regulator gene lugR by the xylAB promoter along with the xylR gene encoding a xylose-sensitive repressor. The erythromycin resistance cassette ermB was integrated for selection purposes.

Extended Data Figure 2 Structure elucidation by multistage tandem and electrospray ionization high-resolution mass spectrometry.

a, A single-stage high-resolution MS/MS experiment revealed a superposition of fragment ions typically found for cyclic peptides. Quasi molecular ion selected for fragmentation is marked with a blue rhombus (m/z = 783.45). For sequence annotation, fragment ions were searched for b-ions of high intensity. One fragmentation route is annotated exemplarily by highlighting respective a-, b- and c-ion series signals. Thia, thiazoldine. b, Data generated by multistage tandem mass spectrometry show that lugdunin mainly fragmented along four routes (blue digits; (I), (II), (III), (IV)). Initial protonation occurs at the secondary amine of thiazolidine (blue H atom). Proton transfer to nearby peptide bonds initiated ring cleavage with subsequent fragmentation. Initial loss of ammonia for fragmentation route (I) can be explained by a precedent six-membered transition state. Intensities are in arbitrary units. Blue rhombuses label the position of initial ring cleavage. Fragmentation route molecules are shown in linearized form.

Extended Data Figure 3 NMR spectra of the natural product lugdunin.

The two diastereomeric and interconvertible forms of lugdunin (see imine intermediate, Extended Data Fig. 4d) show distinctive sets of NMR signals with consistent patterns, which were assigned by two-dimensional NMR methods (COSY, HMBC, HSQC-DEPT, ROESY and TOCSY) and corroborated the thiazolidine heterocycle as a special feature of lugdunin. Chemical shifts (δ) are shown in p.p.m. a, 1H NMR spectrum (600 MHz) of lugdunin in DMSO-d6 at 308 K. b, 13C NMR spectrum (150 MHz) of lugdunin in DMSO-d6 at 308 K. Atom numbering refers to full spectral assignment shown in Extended Data Table 1. c, Expansion of HMBC spectrum (heteronuclear multiple bond correlation) shows distinct correlations between the amino acid α-proton and the carbonyl C-atom of the respective amino acid. d, Expansion of ROESY spectrum (rotation frame nuclear Overhauser effect spectroscopy) shows short-ranged correlations through space between α-protons and amino acid amide protons. e, Taken together, HMBC (green arrows) and ROESY (double headed blue arrows) correlations allowed for a full sequential walk along the peptide backbone, which readily confirmed the amino acid sequence of both lugdunin diastereomers (the sequential walk is exemplarily shown for one diastereomer).

Extended Data Figure 4 The thiazolidine moiety of lugdunin and its formation by peptide cyclisation.

a, Blue rhombus marks the b2-ion from fragmentation route I (Extended Data Fig. 2). The ion was selected from an in-source collision-induced decay (isCID) experiment and was further fragmented in order to find thiazolidine-specific fragment ions. High-resolution MS data are shown with annotated sum formulas and respective deviations from calculated masses (errors in p.p.m.). Shown fragment ions reveal the b1-ion at m/z = 170.0635 Da. Intensity is shown in arbitrary units. b, Photometric detection of thiazolidines at 670 nm. A positive colour reaction with 3-methyl-2-benzothiazolone hydrazone hydrochloride (Sawicki reagent) gives rise to detectable absorbance at 670 nm. Thiazolidine-4-carboxylic acid (thiazolidine) was chosen as positive control, whereas 2-methyl-2-thiazoline (thiazoline) and DMSO acted as negative controls. c, Observable colours for the thiazolidine detection reaction. Thiazolidine-4-carboxlic acid (blue), lugdunin (green) and negative controls (yellow). d, The terminal reductase of LugC is proposed to initiate cleavage of the thioester-bound peptide chain with the aid of an NAD(P)H cofactor. The mature heptapeptide is liberated reductively from the NRPS multienzyme complex and cyclises via the N-terminal amine (l-Cys) and C-terminal aldehyde (l-Val) to form a macrocyclic imine/Schiff base. Subsequent nucleophilic attack of the cysteine thiol group generates the five-membered thiazolidine heterocycle. Nucleophilic attack by the l-cysteine sulfhydryl group may occur either at the re or si face of the imine thus leading to a diastereomeric mixture of two structural populations (depicted with wavy bond). LugC is shown as truncated gene, as indicated by the two lines (||).

Extended Data Figure 5 Lugdunin activity against eukaryotic cells.

a, b, Human neutrophil granulocytes (a) or erythrocytes (b) were incubated with high concentrations of lugdunin. Their lysis was monitored by the release of the enzyme lactate dehydrogenase (a) or haemoglobin (b), respectively. Cells without lugdunin were used as negative control. Incubation of cells in 2% Triton X-100 was used as positive control for high lysis. The data represent three independent experiments ± s.d. c, Promyelocytic leukaemia (HL60) cells were incubated with high concentrations of lugdunin. In order to determine the 50% inhibitory concentration of lugdunin, the metabolic activity of HL60 cells was measured by the conversion of resazurin into the highly fluorescent resorufin. The apoptosis-inducing staurosporine was used as positive control. IC50 values were calculated from the means of three independent experiments.

Source data

Extended Data Figure 6 Time course of incorporation of tritium-labelled metabolic precursors into lugdunin-treated B. subtilis.

B. subtilis 168 (trpC2) is a widely used model organism for mode of action investigations and was also used for orienting studies on the mechanism of lugdunin. Susceptibility of B. subtilis and S. aureus to lugdunin is similar (Table 1), with an MIC for B. subtilis of 4 μg ml−1 in the Belitzky minimal medium used in this assay. ad, Incorporation of thymidine into DNA (a), uridine into RNA (b), leucine into protein (c) or N-acetylglucosamine into peptidoglycan (d) ceased within minutes during lugdunin treatment. The experiment was repeated on three days with three independent bacterial cultures. One representative experiment is shown. At a concentration of half the MIC (1/2 MIC), incorporation of precursors into all pathways ceased reproducibly. At 1/8 MIC, incorporation continued repeatedly in parallel with the untreated control. At 1/4 MIC, the depicted experiment shows protein and peptidoglycan syntheses slightly more impaired than DNA and RNA syntheses, whereas the opposite occurred in another experiment. In summary, all four metabolic pathways seem to be equally impaired by lugdunin.

Source data

Extended Data Figure 7 Nasal colonization rates by S. aureus and S. lugdunensis in cotton rats.

ac, Different inocula of S. aureus Newman (a), S. lugdunensis IVK 28 wild type (b) and S. lugdunensis IVK 28 ΔlugD (c) were instilled intranasally to determine their efficiency to colonize the noses of cotton rats (5 or 6 animals per group). c.f.u. of each strain were determined per nose after 5 days and plotted as individual dots. Lines represent the median of each group.

Source data

Extended Data Table 1 NMR spectral assignment of lugdunin diastereomers
Extended Data Table 2 Primers used in this study

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Zipperer, A., Konnerth, M., Laux, C. et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535, 511–516 (2016). https://doi.org/10.1038/nature18634

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