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Potent and specific antibiotic combination therapy against Clostridioides difficile

Nature Chemical Biology volume 20, pages 924–933 (2024)Cite this article

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Abstract

Keratinicyclins and keratinimicins are recently discovered glycopeptide antibiotics. Keratinimicins show broad-spectrum activity against Gram-positive bacteria, while keratinicyclins form a new chemotype by virtue of an unusual oxazolidinone moiety and exhibit specific antibiosis against Clostridioides difficile. Here we report the mechanism of action of keratinicyclin B (KCB). We find that steric constraints preclude KCB from binding peptidoglycan termini. Instead, KCB inhibits C. difficile growth by binding wall teichoic acids (WTAs) and interfering with cell wall remodeling. A computational model, guided by biochemical studies, provides an image of the interaction of KCB with C. difficile WTAs and shows that the same H-bonding framework used by glycopeptide antibiotics to bind peptidoglycan termini is used by KCB for interacting with WTAs. Analysis of KCB in combination with vancomycin (VAN) shows highly synergistic and specific antimicrobial activity, and that nanomolar combinations of the two drugs are sufficient for complete growth inhibition of C. difficile, while leaving common commensal strains unaffected.

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Fig. 1: Structures of GPAs studied herein and binding assays with the peptidoglycan tripeptide.
Fig. 2: X-ray crystal structures and alignments of KMA and KCB.
Fig. 3: Synergy and TEM analysis of VAN and KCB.
Fig. 4: Interaction of KCB with PS-II, a C. difficile-specific WTA.
Fig. 5: Model for the mode of action of KCB against C. difficile.

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Data availability

Atomic coordinates and structure factors for KMA and KCB have been deposited in the PDB under accession numbers 7LKC and 7LTB, respectively. Other relevant data supporting the findings of this study are available within the Article, source data and supplementary materials. Datasets are also available from the corresponding authors upon reasonable request. Source data are provided with this paper.

References

  1. Antibiotic Resistance Threats in the United States (US Department of Health and Human Services, CDC, 2019).

  2. Fenton, S., Stephenson, D. & Weder, C. Pseudomembranous colitis associated with antibiotic therapy—an emerging entity. Can. Med. Assoc. J. 111, 1110–1111 (1974). 1114.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bartlett, J. G., Chang, T. W., Gurwith, M., Gorbach, S. L. & Onderdonk, A. B. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N. Engl. J. Med. 298, 531–534 (1978).

    CAS  PubMed  Google Scholar 

  4. Theriot, C. M. et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat. Commun. 5, 3114 (2014).

    PubMed  Google Scholar 

  5. Abt, M. C., McKenney, P. T. & Pamer, E. G. Clostridium difficile colitis: pathogenesis and host defence. Nat. Rev. Microbiol. 14, 609–620 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Oksi, J., Anttila, V.-J. & Mattila, E. Treatment of Clostridioides (Clostridium) difficile infection. Ann. Med. 52, 12–20 (2020).

    PubMed  Google Scholar 

  7. Williams, D. H., Williamson, M. P., Butcher, D. W. & Hammond, S. J. Detailed binding sites of the antibiotics vancomycin and ristocetin A: determination of intermolecular distances in antibiotic/substrate complexes by use of the time-dependent NOE. J. Am. Chem. Soc. 105, 1332–1339 (1983).

    CAS  Google Scholar 

  8. Nitanai, Y. et al. Crystal structures of the complexes between vancomycin and cell-wall precursor analogs. J. Mol. Biol. 385, 1422–1432 (2009).

    CAS  PubMed  Google Scholar 

  9. Johnson, S. et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin. Infect. Dis. 59, 345–354 (2014).

    CAS  PubMed  Google Scholar 

  10. Louie, T. J. et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N. Engl. J. Med. 364, 422–431 (2011).

    CAS  PubMed  Google Scholar 

  11. Xu, F. et al. A genetics-free method for high-throughput discovery of cryptic microbial metabolites. Nat. Chem. Biol. 15, 161–168 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Rekharsky, M. et al. Thermodynamics of interactions of vancomycin and synthetic surrogates of bacterial cell wall. J. Am. Chem. Soc. 128, 7736–7737 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gerhard, U., Mackay, J. P., Maplestone, R. A. & Williams, D. H. The role of the sugar and chlorine substituents in the dimerization of vancomycin antibiotics. J. Am. Chem. Soc. 115, 232–237 (1993).

    CAS  Google Scholar 

  14. Mackay, J. P., Gerhard, U., Beauregard, D. A., Maplestone, R. A. & Williams, D. H. Dissection of the contributions toward dimerization of glycopeptide antibiotics. J. Am. Chem. Soc. 116, 4573–4580 (1994).

    CAS  Google Scholar 

  15. Barna, J. C. & Williams, D. H. The structure and mode of action of glycopeptide antibiotics of the vancomycin group. Annu. Rev. Microbiol. 38, 339–357 (1984).

    CAS  PubMed  Google Scholar 

  16. Nicolaou, K. C., Boddy, C. N., Bräse, S. & Winssinger, N. Chemistry, biology, and medicine of the glycopeptide antibiotics. Angew. Chem. Int. Ed. Engl. 38, 2096–2152 (1999).

    CAS  PubMed  Google Scholar 

  17. Kahne, D., Leimkuhler, C., Lu, W. & Walsh, C. Glycopeptide and lipoglycopeptide antibiotics. Chem. Rev. 105, 425–448 (2005).

    CAS  PubMed  Google Scholar 

  18. Perkins, H. R. Specificity of combination between mucopeptide precursors and vancomycin or ristocetin. Biochem. J. 111, 195–205 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Nieto, M. & Perkins, H. R. Modifications of the acyl-d-alanyl-d-alanine terminus affecting complex-formation with vancomycin. Biochem. J. 123, 789–803 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kannan, R. et al. Function of the amino sugar and N-terminal amino acid of the antibiotic vancomycin in its complexation with cell wall peptides. J. Am. Chem. Soc. 110, 2946–2953 (1988).

    CAS  Google Scholar 

  21. Booth, P. M. & Williams, D. H. Preparation and conformational analysis of vancomycin hexapeptide and aglucovancomycin hexapeptide. J. Chem. Soc. Perkin Trans. 1 12, 2335–2339 (1989).

  22. Schäfer, M., Schneider, T. R. & Sheldrick, G. M. Crystal structure of vancomycin. Structure 4, 1509–1515 (1996).

    PubMed  Google Scholar 

  23. Arthur, M. et al. Evidence for in vivo incorporation of d-lactate into peptidoglycan precursors of vancomycin-resistant enterococci. Antimicrob. Agents Chemother. 36, 867–869 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee, J.-G., Sagui, C. & Roland, C. First principles investigation of vancomycin and teicoplanin binding to bacterial cell wall termini. J. Am. Chem. Soc. 126, 8384–8385 (2004).

    CAS  PubMed  Google Scholar 

  25. Lee, J.-G., Sagui, C. & Roland, C. Quantum simulations of the structure and binding of glycopeptide antibiotic aglycons to cell wall analogues. J. Phys. Chem. B. 109, 20588–20596 (2005).

    CAS  PubMed  Google Scholar 

  26. Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 98, 5648–5652 (1993).

    CAS  Google Scholar 

  27. Lee, C., Yang, W. & Parr, R. G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B. 37, 785–789 (1988).

    CAS  Google Scholar 

  28. Tomasi, J., Mennucci, B. & Cammi, R. Quantum mechanical continuum solvation models. Chem. Rev. 105, 2999–3094 (2005).

    CAS  PubMed  Google Scholar 

  29. Avogadro: an open-source molecular builder and visualization tool v.1.20 (Avogadro Chemistry, 2022).

  30. Hanwell, M. D. et al. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform. 4, 17 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rappe, A. K., Casewit, C. J., Colwell, K. S., Goddard, W. A. & Skiff, W. M. UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations. J. Am. Chem. Soc. 114, 10024–10035 (1992).

    CAS  Google Scholar 

  32. Berenbaum, M. C. A method for testing for synergy with any number of agents. J. Infect. Dis. 137, 122–130 (1978).

    CAS  PubMed  Google Scholar 

  33. Yang, J. & Yang, H. Antibacterial activity of Bifidobacterium breve against Clostridioides difficile. Front. Cell Infect. Microbiol. 9, 288 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Deng, H. et al. Bacteroides fragilis prevents Clostridium difficile infection in a mouse model by restoring gut barrier and microbiome regulation. Front. Microbiol. 9, 2976 (2018).

    PubMed  PubMed Central  Google Scholar 

  35. Casas, V. D. L., Miller, S., Herbert, D. L. & Jiang, Z.-D. In vitro effects of probiotics on Clostridium difficile toxin production and sporulation. Int. Arch. Public Health Community Med. 4, 40 (2020).

    Google Scholar 

  36. Campbell, J. et al. An antibiotic that inhibits a late step in wall teichoic acid biosynthesis induces the cell wall stress stimulon in Staphylococcus aureus. Antimicrob. Agents Chemother. 56, 1810–1820 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wenzel, M. et al. A flat embedding method for transmission electron microscopy reveals an unknown mechanism of tetracycline. Commun. Biol. 4, 306 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Mcguire, J. M., Wolfe, R. N. & Ziegler, D. W. Vancomycin, a new antibiotic. II. In vitro antibacterial studies. Antibiot. Annu. 3, 612–618 (1955).

    PubMed  Google Scholar 

  39. Goldstein, B. P. Resistance to rifampicin: a review. J. Antibiot. 67, 625–630 (2014).

    CAS  Google Scholar 

  40. Kim, S. J., Cegelski, L., Preobrazhenskaya, M. & Schaefer, J. Structures of Staphylococcus aureus cell-wall complexes with vancomycin, eremomycin, and chloroeremomycin derivatives by 13C{19F} and 15N{19F} rotational-echo double resonance. Biochemistry 45, 5235–5250 (2006).

    CAS  PubMed  Google Scholar 

  41. Culp, E. J. et al. Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling. Nature 578, 582–587 (2020).

    CAS  PubMed  Google Scholar 

  42. Ganeshapillai, J., Vinogradov, E., Rousseau, J., Weese, J. S. & Monteiro, M. A. Clostridium difficile cell-surface polysaccharides composed of pentaglycosyl and hexaglycosyl phosphate repeating units. Carbohydr. Res. 343, 703–710 (2008).

    CAS  PubMed  Google Scholar 

  43. Campbell, J. et al. Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosyntheses in Staphylococcus aureus. ACS Chem. Biol. 6, 106–116 (2011).

    CAS  PubMed  Google Scholar 

  44. Swoboda, J. G. et al. Discovery of a small molecule that blocks wall teichoic acid biosynthesis in Staphylococcus aureus. ACS Chem. Biol. 4, 875–883 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Willing, S. E. et al. Clostridium difficile surface proteins are anchored to the cell wall using CWB2 motifs that recognise the anionic polymer PSII. Mol. Microbiol. 96, 596–608 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Mitachi, K. et al. Novel FR-900493 analogues that inhibit the outgrowth of Clostridium difficile spores. ACS Omega 3, 1726–1739 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Lebedev, A. A. et al. JLigand: a graphical tool for the CCP4 template-restraint library. Acta Crystallogr. D. Biol. Crystallogr. 68, 431–440 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Honorato, R. V. et al. Structural biology in the clouds: the WeNMR-EOSC ecosystem. Front. Mol. Biosci. 8, 729513 (2021).

    PubMed  PubMed Central  Google Scholar 

  49. van Zundert, G. C. P. et al. The HADDOCK2.2 web server: user-friendly integrative modeling of biomolecular complexes. J. Mol. Biol. 428, 720–725 (2016).

    PubMed  Google Scholar 

  50. Dominguez, C., Boelens, R. & Bonvin, A. M. J. J. HADDOCK: a protein–protein docking approach based on biochemical or biophysical information. J. Am. Chem. Soc. 125, 1731–1737 (2003).

    CAS  PubMed  Google Scholar 

  51. Abraham, M. J., van der Spoel, D., Lindahl, E., Hess, B. & the GROMACS Development Team. GROMACS User Manual version 2019.3 (GROMACS, 2019).

  52. Lindorff-Larsen, K. et al. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 78, 1950–1958 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Abraham, M. J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2, 19–25 (2015).

    Google Scholar 

  54. Atilano, M. L. et al. Teichoic acids are temporal and spatial regulators of peptidoglycan cross-linking in Staphylococcus aureus. Proc. Natl Acad. Sci. USA 107, 18991–18996 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Usenik, A. et al. The CWB2 cell wall-anchoring module is revealed by the crystal structures of the Clostridium difficile cell wall proteins Cwp8 and Cwp6. Structure 25, 514–521 (2017).

    CAS  PubMed  Google Scholar 

  56. Yu, F. et al. Glycopeptide antibiotic teicoplanin inhibits cell entry of SARS-CoV-2 by suppressing the proteolytic activity of cathepsin L. Front. Microbiol. 13, 884034 (2022).

    PubMed  PubMed Central  Google Scholar 

  57. Kwon, Y.-J., Kim, H.-J. & Kim, W.-G. Complestatin exerts antibacterial activity by the inhibition of fatty acid synthesis. Biol. Pharm. Bull. 38, 715–721 (2015).

    CAS  PubMed  Google Scholar 

  58. Kaneko, I., Fearon, D. T. & Austen, K. F. Inhibition of the alternative pathway of human complement in vitro by a natural microbial product, complestatin. J. Immunol. 124, 1194–1198 (1980).

    CAS  PubMed  Google Scholar 

  59. Olsen, M. A., Yan, Y., Reske, K. A., Zilberberg, M. D. & Dubberke, E. R. Recurrent Clostridium difficile infection is associated with increased mortality. Clin. Microbiol. Infect. 21, 164–170 (2015).

    CAS  PubMed  Google Scholar 

  60. Enoch, D. A. et al. Risk of complications and mortality following recurrent and non-recurrent Clostridioides difficile infection: a retrospective observational database study in England. J. Hosp. Infect. 106, 793–803 (2020).

    CAS  PubMed  Google Scholar 

  61. Kabsch, W. XDS. Acta Crystallogr. D. Biol. Crystallogr. 66, 125–132 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Evans, P. R. & Murshudov, G. N. How good are my data and what is the resolution? Acta Crystallogr. D. Biol. Crystallogr. 69, 1204–1214 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Sheldrick, G. M. Experimental phasing with SHELXC/D/E: combining chain tracing with density modification. Acta Crystallogr. D. Biol. Crystallogr. 66, 479–485 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D. Biol. Crystallogr. 66, 486–501 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D. Biol. Crystallogr. 66, 213–221 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Vanommeslaeghe, K., Raman, E. P. & MacKerell, A. D. Jr. Automation of the CHARMM general force field (CGenFF) II: assignment of bonded parameters and partial atomic charges. J. Chem. Inf. Model. 52, 3155–3168 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Frisch, M. J. et al. Gaussian 09 Rev. E.01 (Gaussian Inc., 2009).

  69. Grimme, S., Antony, J., Ehrlich, S. & Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 132, 154104 (2010).

    PubMed  Google Scholar 

  70. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically (Clinical and Laboratory Standards Institute, 2018).

  71. CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria (Clinical and Laboratory Standards Institute, 2018).

  72. Krogstad, D. J. & Moellering, R. C. Jr in Antibiotics in Laboratory Medicine (ed. Lorian, V.) 537–595 (Williams & Wilkins Co., 1986).

  73. Schaub, R. E. & Dillard, J. P. Digestion of peptidoglycan and analysis of soluble fragments. Bio-Protoc. 7, e2438 (2017).

    PubMed  PubMed Central  Google Scholar 

  74. Schüttelkopf, A. W. & van Aalten, D. M. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D. Biol. Crystallogr. 60, 1355–1363 (2004).

    PubMed  Google Scholar 

  75. Bayly, C. I., Cieplak, P., Cornell, W. & Kollman, P. A. A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model. J. Phys. Chem. 97, 10269–10280 (1993).

    CAS  Google Scholar 

  76. Frisch, M. J. et al. Gaussian 16 Rev. C.01 (Gaussian Inc., 2016).

  77. Sousa da Silva, A. W. & Vranken, W. F. ACPYPE—antechamber Python parser interface. BMC Res. Notes 5, 367 (2012).

    PubMed  PubMed Central  Google Scholar 

  78. Hess, B., Kutzner, C., van der Spoel, D. & Lindahl, E. GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory Comput. 4, 435–447 (2008).

    CAS  PubMed  Google Scholar 

  79. Hess, B. P-LINCS: a parallel linear constraint solver for molecular simulation. J. Chem. Theory Comput. 4, 116–122 (2008).

    CAS  PubMed  Google Scholar 

  80. Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to V. Vandavasi at Princeton University’s Biophysics Core Facility for assistance with ITC experiments, J. Musaev and A. Kaledin at Emory University’s Cherry L. Emerson Center for Scientific Computation for assistance with DFT calculations and MD simulations, as well as the Edward C. Taylor 3rd Year Fellowship in Chemistry (to V.T.C.) and the National Institutes of Health (grant nos. 1R35GM147557 to K.M.D. and 1R01GM129496 to M.R.S.) for support of this work.

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  1. These authors contributed equally: Vasiliki T. Chioti, Kirklin L. McWhorter.

Authors and Affiliations

  1. Department of Chemistry, Princeton University, Princeton, NJ, USA

    Vasiliki T. Chioti, Yuchen Li, Katherine M. Davis & Mohammad R. Seyedsayamdost

  2. Department of Chemistry, Emory University, Atlanta, GA, USA

    Kirklin L. McWhorter & Tamra C. Blue

  3. Institute of Pharmaceutical Biotechnology and Department of Gastroenterology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Fei Xu

  4. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Philip D. Jeffrey & Mohammad R. Seyedsayamdost

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Contributions

V.T.C., K.L.M., K.M.D. and M.R.S. conceived of the study. V.T.C. performed all biochemical experiments with assistance from Y.L. on the TEM studies. K.L.M. conducted all computational experiments with assistance from T.C.B. on the MD simulations. F.X. provided KCB for crystallographic studies. K.M.D. and P.D.J. solved the crystal structure of KCB. V.T.C., K.L.M., K.M.D. and M.R.S. wrote the manuscript with contributions from all authors.

Corresponding authors

Correspondence to Katherine M. Davis or Mohammad R. Seyedsayamdost.

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M.R.S. is a co-founder of Cryptyx Bioscience. Some of the authors have filed a provisional patent application related to this project.

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Supplementary information

Supplementary Information

Supplementary Tables 1–13 and Figs. 1–16.

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Supplementary Video

Animation of the alignment of KMA and KCB. Monomer A is displayed for each GPA.

Supplementary Data

Statistical source data for Supplementary Figs. 1, 4–6, 8, 11 and 14–16.

Source data

Source Data Fig. 1

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

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Chioti, V.T., McWhorter, K.L., Blue, T.C. et al. Potent and specific antibiotic combination therapy against Clostridioides difficile. Nat Chem Biol 20, 924–933 (2024). https://doi.org/10.1038/s41589-024-01651-z

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