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

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 bioterrorism(3). 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 virulence(10). 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.