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

Research output: Contribution to journalLetterpeer-review

233 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 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.

Original languageEnglish
Pages (from-to)29-32
Number of pages4
JournalNature Chemical Biology
Volume1
Issue number1
DOIs
StatePublished - Jun 2005

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