Antibiotics targeting siderophore receptors

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 DESCRIPTION (provided by applicant): Antibiotic-resistant Enterobacteriaceae, including carbapenem-resistant and extended spectrum β-lactamase producing Klebsiella spp., Escherichia coli, and Enterobacter spp. are considered by the Centers for Disease Control and Prevention (CDC) to be urgent and serious health threats to the United States. Our long term goal is to develop and evaluate novel antibiotics for the Enterobacteriaceae. We will attain our goal with nanoparticle and dendrimeric siderophore plugs. Siderophores are powerful iron chelators synthesized and excreted by microorganisms to sequester and return the iron needed for their growth. All Enterobacteriaceae rely primarily on the siderophore enterobactin for their iron acquisition. Because iron is a limiting factor in bacterial growth in the human body (includin on skin and in blood, urine and cerebrospinal fluid), this siderophore has long been established as a virulence factor for all Enterobacteriaceae. Increased expression of the outer-membrane siderophore receptors for enterobactin, FepA, has been repeatedly observed during infection with all the virulent strains of the Enterobacteriaceae. Our central hypothesis is that siderophore anchors that block the siderophore transport systems of the Enterobacteriaceae will significantly reduce the virulence of the bacteria by starving it. The overall objective of this application is t synthesize and evaluate a new family of enterobactin plugs as antibiotics for the treatment of the Enterobacteriaceae. The rationale for the proposed research is that the availability of more powerful antibiotics and antibiotics with novel modes of actions is necessary to treat increasingly prevalent bacterial pathogens that are resistant to current drugs. We plan to accomplish our objectives by pursuing the following Specific Aims: 1) Synthesize enterobactin plugs that block the FepA receptor; and 2) Evaluate the potential of enterobactin plugs as antibiotics. This research is significant because it aims to develop a new class of antibiotics that exploits a novel mechanism of action and that targets microorganisms, which present urgent and serious threats, that are resistant to current classes of antibiotics. Our approach is innovative because we are exploiting the siderophore receptor itself as a target for antibiotics with novel mechanisms of actions. The transporters involved in the uptake of iron themselves have not yet been evaluated as targets for antibiotics.