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Zentralinstitut für Ernährungs- und Lebensmittelforschung (ZIEL)

Abteilung Mikrobiologie
Technische Universität München
Weihenstephaner Berg 3
D-85350 Freising


Angew Chem Int Ed Engl. 2018 Oct 26;57(44):14619-14623. 
doi: 10.1002/anie.201807442. Epub 2018 Oct 2.

Reprogramming Human Siderocalin To Neutralize Petrobactin, the Essential Iron Scavenger of Anthrax Bacillus.
Dauner M1, Eichinger A1, Lücking G2, Scherer S2, Skerra A1.

1 Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer- 
   Forum 5, 85354, Freising, Germany.

2 Lehrstuhl für Mikrobielle Ökologie, Technische Universität München, Weihenstephaner
   Berg 3, 85354, Freising, Germany.

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 PBFeIII instead of BBFeIII , and with even higher affinity (KD ≈20?pm). X-ray crystallographic analysis of the resulting "petrocalin" in complex with PBGaIII 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.

KEYWORDS: anticalin; iron chelator; lipocalin; protein engineering; siderophore

DOI: 10.1002/anie.201807442


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