Structural Basis for Xenosiderophore Utilization by the Human Pathogen Staphylococcus aureus

ACS Infectious Diseases
Nathaniel P EndicottTimothy A Wencewicz

Abstract

Staphylococcus aureus produces a cocktail of metallophores (staphylopine, staphyloferrin A, and staphyloferrin B) to scavenge transition metals during infection of a host. In addition, S. aureus displays the extracellular surface lipoproteins FhuD1 and FhuD2 along with the ABC transporter complex FhuCBG to facilitate the use of hydroxamate xenosiderophores such as desferrioxamine B (DFOB) for iron acquisition. DFOB is used as a chelation therapy to treat human iron overload diseases and has been linked to an increased risk of S. aureus infections. We used a panel of synthetic DFOB analogs and a FhuD2-selective trihydroxamate sideromycin to probe xenosiderophore utilization in S. aureus and establish structure-activity relationships for Fe(III) binding, FhuD2 binding, S. aureus growth promotion, and competition for S. aureus cell entry. Fe(III) binding assays and FhuD2 intrinsic fluorescence quenching experiments revealed that diverse chemical modifications of the terminal ends of linear ferrioxamine siderophores influences Fe(III) affinity but not FhuD2 binding. Siderophore-sideromycin competition assays and xenosiderophore growth promotion assays revealed that S. aureus SG511 and ATCC 11632 can distinguish between competing si...Continue Reading

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Citations

Aug 15, 2018·Chemical Communications : Chem Comm·Tomas Richardson-Sanchez, Rachel Codd
Apr 5, 2020·International Journal of Molecular Sciences·Marialaura MarchettiLuca Ronda
Sep 28, 2020·Pharmacology & Therapeutics·Anutthaman ParthasarathyKarunakaran Kalesh
Jun 11, 2021·ACS Infectious Diseases·Tabbetha J BohacTimothy A Wencewicz
Oct 4, 2019·Journal of Medicinal Chemistry·Apurva PandeyEszter Boros
May 11, 2019·Microbes and Infection·Bianca Silva Vieira de SouzaJuliana Alves Parente-Rocha
Nov 9, 2017·The Journal of Organic Chemistry·Jian ZhangXiaoguang Lei
Sep 14, 2017·The Journal of Organic Chemistry·Sandip SenguptaTaebo Sim
Apr 29, 2020·ACS Central Science·Nathaniel P EndicottTimothy A Wencewicz
Nov 29, 2017·ACS Chemical Biology·Rachel CoddMichael P Gotsbacher

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