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Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis

Nature Chemical Biology volume 1, pages 29–32 (2005)Cite this article

Abstract

Mycobacterium tuberculosis and Yersinia pestis, the causative agents of tuberculosis and plague, respectively, are pathogens with serious ongoing impact on global public health1,2 and potential use as agents of bioterrorism3. Both pathogens have iron acquisition systems based on siderophores, secreted iron-chelating compounds with extremely high Fe3+ affinity4,5. Several lines of evidence suggest that siderophores have a critical role in bacterial iron acquisition inside the human host6,7,8,9, where the free iron concentration is well below that required for bacterial growth and virulence10. Thus, siderophore biosynthesis is an attractive target in the development of new antibiotics to treat tuberculosis and plague2,5,8,11. In particular, such drugs, alone or as part of combination therapies, could provide a valuable new line of defense against intractable multiple-drug-resistant infections. Here, we report the design, synthesis and biological evaluation of a mechanism-based inhibitor of domain salicylation enzymes required for siderophore biosynthesis in M. tuberculosis and Y. pestis. This new antibiotic inhibits siderophore biosynthesis and growth of M. tuberculosis and Y. pestis under iron-limiting conditions.

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Figure 1: Structures of salicyl-capped siderophores, aroyl-adenylate biosynthesis intermediates, and intermediate mimics.
Figure 2: Inhibition of MbtA, YbtE and PchD by salicyl-AMS.
Figure 3: Inhibition of siderophore production and bacterial growth by salicyl-AMS.

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Acknowledgements

We dedicate this paper to Professor Christopher T. Walsh on the occasion of his 60th birthday. We thank R. Perry (University of Kentucky) for critical advice on Y. pestis experiments and G. Sukenick, A. Dudkina, H. Fang and S. Rusli (MSKCC Analytical Core Facility) and C. Soll (Hunter College/City University of New York MS Facility) for mass spectral analyses. D.S.T. acknowledges financial support from the William Randolph Hearst Fund in Experimental Therapeutics, William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of MSKCC. L.E.N.Q, a Scholar of the Stavros S. Niarchos Foundation, acknowledges the financial support of the Potts Memorial Foundation, the Cystic Fibrosis Association and the William Randolph Hearst Foundation.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Ave., Box 62, New York, 10021, New York, USA

    Julian A Ferreras, Federico Di Lello & Luis E N Quadri

  2. Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 422, New York, 10021, New York, USA

    Jae-Sang Ryu & Derek S Tan

  3. Tri-Institutional Research Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 422, New York, 10021, New York, USA

    Derek S Tan

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  1. Julian A Ferreras
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  2. Jae-Sang Ryu
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Correspondence to Derek S Tan or Luis E N Quadri.

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Supplementary information

Supplementary Fig. 1

Structural analysis of aroyl adenylate binding to adenylate-forming enzymes. (PDF 5349 kb)

Supplementary Fig. 2

Synthesis of salicyl-AMS. (PDF 621 kb)

Supplementary Methods (PDF 377 kb)

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Ferreras, J., Ryu, JS., Di Lello, F. et al. Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat Chem Biol 1, 29–32 (2005). https://doi.org/10.1038/nchembio706

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