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Monobactam formation in sulfazecin by a nonribosomal peptide synthetase thioesterase

Nature Chemical Biology volume 14, pages 5–7 (2018)Cite this article

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Abstract

The N-sulfonated monocyclic β-lactam ring characteristic of the monobactams confers resistance to zinc metallo-β-lactamases and affords the most effective class to combat carbapenem-resistant enterobacteria (CRE). Here we report unprecedented nonribosomal peptide synthetase activities, wherein an assembled tripeptide is N-sulfonated in trans before direct synthesis of the β-lactam ring in a noncanonical, cysteine-containing thioesterase domain. This means of azetidinone synthesis is distinct from the three others known in nature.

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Figure 1: Alternative potential biosynthetic routes to monobactam synthesis in sulfazecin.
Figure 2: M3-catalyzed monobactam formation.

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NCBI Reference Sequence

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Acknowledgements

This work was supported by the NIH (AI014937 and AI121072). We thank J. Liu of the University of North Carolina, Chapel Hill for providing DNA encoding PAPS synthesis proteins and I.P. Mortimer at the Johns Hopkins Mass Spectroscopy Facility for UPLC–HRMS data.

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Authors and Affiliations

  1. Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland, USA

    Ryan A Oliver, Rongfeng Li & Craig A Townsend

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  1. Ryan A Oliver
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  2. Rongfeng Li
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  3. Craig A Townsend
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Contributions

C.A.T. and R.A.O. designed and directed the study. R.A.O. carried out the syntheses and biochemical reactions. R.A.O. and R.F.L. cloned and expressed proteins. All authors analyzed the data and discussed the results. R.A.O., R.F.L., and C.A.T. prepared the manuscript.

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Correspondence to Craig A Townsend.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Results, Supplementary Table 1, Supplementary Figures 1–14 (PDF 9731 kb)

Life Sciences Reporting Summary (PDF 129 kb)

Supplementary Note

General synthetic methods (PDF 2744 kb)

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Oliver, R., Li, R. & Townsend, C. Monobactam formation in sulfazecin by a nonribosomal peptide synthetase thioesterase. Nat Chem Biol 14, 5–7 (2018). https://doi.org/10.1038/nchembio.2526

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