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Publication Abstract from PubMed

Bacillus anthracis constitutes a dangerous biohazard which, apart from specific toxins, owes its pronounced virulence to a two-pronged import mechanism for FeIII ions, which are scarce in body fluids. This pathogenic bacterium secretes a pair of siderophores, bacillibactin (BB) and petrobactin (PB), of which only BB is bound and neutralized by the human siderocalin, an abundant lipocalin protein in human plasma. We describe the reshaping of siderocalin by combinatorial and rational protein engineering to specifically bind PB*FeIII instead of BB*FeIII, and with even higher affinity (KD approximately 20 pM). X-ray crystallographic analysis of the resulting "petrocalin" in complex with PB*GaIII reveals a positively charged ligand pocket dominated by two Lys and two Arg side chains, of which Arg100 also forms two hydrogen bonds to the central carboxyl and hydroxyl groups of PB. Furthermore, the extended butterfly-like conformation of the PB metal-chelate complex, first elucidated in this study, provides a rationale for the missing recognition by the natural siderocalin. Finally, microbiological studies demonstrate that a combination of petrocalin and siderocalin effectively suppresses the growth of a BB+/PB+ strain of Bacillus cereus under iron-limiting culture conditions. Thus, our engineered lipocalin may offer novel treatment options for devastating infections caused by B. anthracis.

Reprogramming human siderocalin to neutralize petrobactin, the essential iron scavenger of Anthrax bacillus.,Dauner M, Eichinger A, Lucking G, Scherer S, Skerra A Angew Chem Int Ed Engl. 2018 Jul 31. doi: 10.1002/anie.201807442. PMID:30063283^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.