Abstract
Bacillus anthracis owes its pronounced virulence-apart from specific toxins-to a twofold import mechanism for FeIII ions. This pathogenic bacterium secretes the siderophores bacillibactin (BB) and petrobactin (PB), of which only BB is neutralized by human siderocalin, an abundant lipocalin in plasma. We describe its reshaping via combinatorial protein design to bind PB⋅FeIII instead of BB⋅FeIII , and with even higher affinity (KD ≈20 pm). X-ray crystallographic analysis of the resulting "petrocalin" in complex with PB⋅GaIII reveals a positively charged ligand pocket while the extended butterfly-like conformation of the bound PB provides a rationale for the missing recognition by the natural siderocalin. In microbiological studies, a combination of petrocalin and siderocalin effectively suppressed the growth of a BB+ /PB+ strain of Bacillus cereus under iron-limiting culture conditions. Thus, our reprogrammed lipocalin may offer novel treatment options for devastating infections caused by B. anthracis.
Published Version
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