Desarrollo de un inhibidor de unión fuerte de la síntesis de sideróforos en "Yersinia pestis" y "Mycobacterium tuberculosis"

Abstract

The causative agents of tuberculosis and plague, M. tuberculosis and Y. pestis respectively, represent a serious problem for global public health. Although tuberculosis is curable, 2 millions people die because of this disease every year. It is estimated that one third of the world’s population is infected with M. tuberculosis and approximately 9 million people per year become sick with active tuberculosis. In contrast to tuberculosis, plague has a low incidence with approximately 2000 to 3000 cases are reported every year globally. However, the appearance of multiresistent strains, the very high mortality if left untreated, and the deterioration of living conditions in many parts of the world that favor the spread of the disease allow human plague to remain a serious threat to public health. Because Y. pestis is very contagious via aerosols, it has the potential to be used as agent for bioterrorism further increasing their threat to global public health. There is evidence that both microorganisms depend on iron, among other things, to establish a successful infection. As a mechanism of defense, hosts reduce iron availability by binding it to different molecules. To overcome this limitation, bacteria synthesize and release iron-chelating compounds, so-called siderophores, with an extremely high affinity for ferric ions. Thus, siderophore biosynthesis represents a very good target for the development of antibiotics to treat tuberculosis and plague. In this work we report the design, synthesis and evaluation in both enzyme and cell-based assays, of an inhibitor of the first step of the biosynthesis of the siderophores of M. tuberculosis and Y. pestis. We show that this inhibitor behaves as a tight binding inhibitor of the enzymes responsible for the adenylation of salicylic acid, and that it inhibits the synthesis of siderophores and consequently the growth of M. tuberculosis and Y. pestis under iron-limiting conditions. To our knowledge, this compound is the first biochemically confirmed inhibitor of siderophore biosynthesis