Small-Molecule Inhibition of Siderophore Biosynthesis in Mycobacterium Tuberculosis and Yersinia Pestis

Julian A. Ferreras; Jae Sang Ryu; Federico Di Lello; Derek S. Tan; Luis E.N. Quadri

doi:10.1038/nchembio706

Small-Molecule Inhibition of Siderophore Biosynthesis in Mycobacterium Tuberculosis and Yersinia Pestis

Julian A. Ferreras, Jae Sang Ryu, Federico Di Lello, Derek S. Tan, Luis E.N. Quadri

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Letter › peer-review

246 Scopus citations

Abstract

Mycobacterium tuberculosis and Yersinia pestis, the causative agents of tuberculosis and plague, respectively, are pathogens with serious ongoing impact on global public health^1,2 and potential use as agents of bioterrorism³. Both pathogens have iron acquisition systems based on siderophores, secreted iron-chelating compounds with extremely high Fe³⁺ affinity^4,5. Several lines of evidence suggest that siderophores have a critical role in bacterial iron acquisition inside the human host^6-9, 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 plague^2,5,8,11. 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.

Original language	English
Pages (from-to)	29-32
Number of pages	4
Journal	Nature Chemical Biology
Volume	1
Issue number	1
DOIs	https://doi.org/10.1038/nchembio706
State	Published - Jun 2005

Bibliographical note

Funding Information:
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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title = "Small-Molecule Inhibition of Siderophore Biosynthesis in Mycobacterium Tuberculosis and Yersinia Pestis",

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 host6-9, 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.",

author = "Ferreras, {Julian A.} and Ryu, {Jae Sang} and {Di Lello}, Federico and Tan, {Derek S.} and Quadri, {Luis E.N.}",

note = "Funding Information: 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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AU - Ferreras, Julian A.

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AU - Tan, Derek S.

AU - Quadri, Luis E.N.

N1 - Funding Information: 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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N2 - 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 host6-9, 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.

AB - 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 host6-9, 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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Small-Molecule Inhibition of Siderophore Biosynthesis in Mycobacterium Tuberculosis and Yersinia Pestis

Abstract

Bibliographical note

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