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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cole, S.T., Eisenach, K.D., McMurray, D.N. & Jacobs, W.R.J. (eds) Tuberculosis and the Tubercle Bacillus (ASM Press, Washington, DC, 2005).
Perry, R.D. & Fetherston, J.D. Yersinia pestis—etiologic agent of plague. Clin. Microbiol. Rev. 10, 35–66 (1997).
Centers for Disease Control and Prevention. Biological and chemical terrorism: strategic plan for preparedness and response. Recommendations of the CDC strategic planning workgroup. MMWR Recomm. Rep. 49, 1–14 (2000).
Perry, R.D., Balbo, P.B., Jones, H.A., Fetherston, J.D. & DeMoll, E. Yersiniabactin from Yersinia pestis: biochemical characterization of the siderophore and its role in iron transport and regulation. Microbiology 145, 1181–1190 (1999).
Quadri, L.E.N. & Ratledge, C. Iron metabolism in the tubercle bacillus and other mycobacteria. in Tuberculosis and the Tubercle Bacillus (eds Cole, S.T., Eisenach, K.D., McMurray, D.N. & Jacobs, W.R.J.) 341–357 (ASM Press, Washington, DC, 2004).
Bearden, S.W., Fetherston, J.D. & Perry, R.D. Genetic organization of the yersiniabactin biosynthetic region and construction of avirulent mutants in Yersinia pestis. Infect. Immun. 65, 1659–1668 (1997).
Gobin, J. & Horwitz, M.A. Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M. tuberculosis cell wall. J. Exp. Med. 183, 1527–1532 (1996).
De Voss, J.J. et al. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc. Natl. Acad. Sci. USA 97, 1252–1257 (2000).
Smith, I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin. Microbiol. Rev. 16, 463–496 (2003).
Jurado, R.L. Iron, infections, and anemia of inflammation. Clin. Infect. Dis. 25, 888–895 (1997).
NIH-NIAID. The counter-bioterrorism research agenda of the National Institute of Allergy and Infections Diseases (NIAID) for CDC category A agents (National Institutes of Health, Bethesda, Maryland, USA, 2002).
Quadri, L.E.N. Assembly of aryl-capped siderophores by modular peptide synthetases and polyketide synthases. Mol. Microbiol. 37, 1–12 (2000).
Crosa, J.H. & Walsh, C.T. Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol. Mol. Biol. Rev. 66, 223–249 (2002).
Quadri, L.E.N., Sello, J., Keating, T.A., Weinreb, P.H. & Walsh, C.T. Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chem. Biol. 5, 631–645 (1998).
Gehring, A.M., Mori, I.I., Perry, R.D. & Walsh, C.T. The nonribosomal peptide synthetase HMWP2 forms a thiazoline ring during biogenesis of yersiniabactin, an iron-chelating virulence factor of Yersinia pestis. Biochemistry 37, 11637–11650 (1998).
Kim, S., Lee, S.W., Choi, E.C. & Choi, S.Y. Aminoacyl-tRNA synthetases and their inhibitors as a novel family of antibiotics. Appl. Microbiol. Biotechnol. 61, 278–288 (2003).
Finking, R. et al. Aminoacyl adenylate substrate analogues for the inhibition of adenylation domains of nonribosomal peptide synthetases. ChemBioChem 4, 903–906 (2003).
Florini, J.R., Bird, H.H. & Bell, P.H. Inhibition of protein synthesis in vitro and in vivo by nucleocidin, an antitrypanosomal antibiotic. J. Biol. Chem. 241, 1091–1098 (1966).
Quadri, L.E.N., Keating, T.A., Patel, H.M. & Walsh, C.T. Assembly of the Pseudomonas aeruginosa nonribosomal peptide siderophore pyochelin: in vitro reconstitution of aryl-4,2-bisthiazoline synthetase activity from PchD, PchE, and PchF. Biochemistry 38, 14941–14954 (1999).
May, J.J., Kessler, N., Marahiel, M.A. & Stubbs, M.T. Crystal structure of DhbE, an archetype for aryl acid activating domains of modular nonribosomal peptide synthetases. Proc. Natl Acad. Sci. USA 99, 12120–12125 (2002).
Copeland, R.A. Tight binding inhibitors. in Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis 305–317 (Wiley-VCH, New York, 2000).
Zhu, X.-F., Williams, H.J. & Scott, A.I. Facile and highly selective 5′-desilylation of multi-silylated nucleosides. J. Chem. Soc. Perkin Trans. I 2305–2306 (2000).
Castro-Pichel, J., Garcia-Lopez, M.T. & De las Heras, F.G. A facile synthesis of ascamycin and related analogs. Tetrahedron 43, 383–389 (1987).
Forrest, A.K. et al. Aminoalkyl adenylate and aminoacyl sulfamate intermediate analogues differing greatly in affinity for their cognate Staphylococcus aureus aminoacyl tRNA synthetases. Bioorg. Med. Chem. Lett. 10, 1871–1874 (2000).
Darwin, K.H., Ehrt, S., Gutierrez-Ramos, J.C., Weich, N. & Nathan, C.F. The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302, 1963–1966 (2003).
Barclay, R. & Ratledge, C. Mycobactins and exochelins of Mycobacterium tuberculosis, M. bovis, M. africanum and other related species. J. Gen. Microbiol. 134, 771–776 (1988).
Gong, S., Bearden, S.W., Geoffroy, V.A., Fetherston, J.D. & Perry, R.D. Characterization of the Yersinia pestis Yfu ABC inorganic iron transport system. Infect. Immun. 69, 2829–2837 (2001).
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nchembio706
This article is cited by
-
On the coordination chemistry of a bacterial siderophore cepabactin from a theoretical perspective
Journal of Molecular Modeling (2023)
-
Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD
JBIC Journal of Biological Inorganic Chemistry (2022)
-
Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling
Scientific Reports (2020)
-
Defining new chemical space for drug penetration into Gram-negative bacteria
Nature Chemical Biology (2020)
-
Targeting adenylate-forming enzymes with designed sulfonyladenosine inhibitors
The Journal of Antibiotics (2019)