Letter abstract
Nature Chemical Biology 1, 29 - 32 (2005)
Published online: 24 May 2005 | doi:10.1038/nchembio706
Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis
Julian A Ferreras1, Jae-Sang Ryu2, Federico Di Lello1, Derek S Tan2,3 & Luis E N Quadri1
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.
- Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Ave., Box 62, New York, New York 10021, USA.
- Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 422, New York, New York 10021, USA.
- Tri-Institutional Research Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 422, New York, New York 10021, USA.
Correspondence to: Luis E N Quadri1 e-mail: leq2001@med.cornell.edu
Correspondence to: Derek S Tan2,3 e-mail: tand@mskcc.org
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Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestisNature Chemical Biology Letter (01 Jun 2005)
