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Lookup NU author(s): Dr Kesha Josts
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
The outer membrane of gram-negative bacteria prevents many antibiotics from reaching intracellular targets. However, some antimicrobials can take advantage of iron import transporters to cross this barrier. We showed previously that the thiopeptide antibiotic thiocillin exploits the nocardamine xenosiderophore transporter, FoxA, of the opportunistic pathogen Pseudomonas aeruginosa for uptake. Here, we show that FoxA also transports the xenosiderophore bisucaberin and describe at 2.5 Å resolution the crystal structure of bisucaberin bound to FoxA. Bisucaberin is distinct from other siderophores because it forms a 3:2 rather than 1:1 siderophore–iron complex. Mutations in a single extracellular loop of FoxA differentially affected nocardamine, thiocillin, and bisucaberin binding, uptake, and signal transduction. These results show that in addition to modulating ligand binding, the extracellular loops of siderophore transporters are of fundamental importance for controlling ligand uptake and its regulatory consequences, which have implications for the development of siderophore–antibiotic conjugates to treat difficult infections.
Author(s): Chan DCK, Josts I, Koteva K, Wright GD, Tidow H, Burrows LL
Publication type: Article
Publication status: Published
Journal: Proceedings of the National Academy of Sciences
Year: 2023
Volume: 120
Issue: 16
Print publication date: 18/04/2023
Online publication date: 12/04/2023
Acceptance date: 07/03/2023
Date deposited: 11/06/2024
ISSN (print): 0027-8424
ISSN (electronic): 1091-6490
Publisher: National Academy of Sciences
URL: https://doi.org/10.1073/pnas.2221253120
DOI: 10.1073/pnas.2221253120
Data Access Statement: Structural data have been deposited in the Protein Data Bank, http://wwpdb.org (PDB ID code 8B43). All other data are available in the supporting information
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