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Anthrax bacteria’s biosynthesis has potential for the development of therapeutic treatmentsBacterial pathogenesis (development of disease) involves three steps: invasion, growth, and disease manifestation. Intervention at any single point to halt disease development requires an understanding of the means the bacteria use to persist and/or proliferate in the host. Methods to interrupt the biosynthesis of molecules that pathogenic bacteria need for survival present opportunities to develop therapeutic treatments for disease. Bacteria synthesize small molecules, called siderophores, to bind extracellular iron ions for transport into the cell. The iron ions are needed for cellular functions. Anthrax (Bacillus anthracis) and the related pathogenic bacteria (Bacillus cereus) synthesize the siderophore petrobactin (Figure 1), which contains the unusual 3,4-dihydroxybenzoyl (3,4-DHB) iron-binding groups. Petrobactin is a “stealth” siderophore because it evades the mammalian immune system and also facilitates the growth and proliferation of the bacteria in a mammalian host. Therefore, targeted inhibition of the enzymes that the bacteria use to synthesize petrobactin has potential for the development of a novel class of anti-anthrax therapeutics. 
Figure 1. Pictoral summary of the genes responsible for petrobactin biosynthesis. Conversion of structure (1) to the 3,4-DHB structure (2) by the enzyme AsbF and subsequent incorporation into petrobactin (3) by the remaining Asb gene products. The gene encoding AsbF is highlighted in red and is part of the asbABCDEF gene cluster. David Fox and Andrew Koppisch (both in B-8) and their collaborators at the National University in Singapore have made the first report and characterization of a new class of enzyme, dehydroshikimate dehydratase (Class II DHSase). Anthrax bacteria synthesize DHSase as part of the vital biosynthetic pathway to the siderophore petrobactin. This enzyme, AsbF, was the final enzyme that had not been characterized in the petrobactin biosynthetic pathway (Figure 1). Based on this and previous studies, the team now has the ability to directly target petrobactin biosynthetic enzymes for discovery of novel therapeutics as well understanding iron-acquisition in Bacillus bacteria. Reference: “The Missing Link to Petrobactin: asbF Encodes a (-)-3-Dehydroshikimate Dehydratase”, Biochemistry (Rapid Report) 47, 12251-12253 (2008). The Biochemistry home page featured this Rapid Report. LDRD and an Agnew National Security Postdoctoral Fellowship supported the LANL work. |
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