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Structure and function of the PiuA and PirA siderophore-drug receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

DOI: 10.1128/AAC.02531-16 DOI Help

Authors: Lucile Moynie (University of St Andrews) , Alexandre Luscher (University Hospital Geneva; University of Geneva) , Dora Rolo (University of Geneva; Universitat de Barcelona) , Daniel Pletzer (Jacobs University) , Antoni Tortajada (University of St Andrews) , Helge Weingart (Jacobs University) , Yvonne Braun (Jacobs University) , Malcolm G. P. Page (Basilea Pharmaceutica International Ltd) , James Naismith (University of St. Andrews) , Thilo Köhler (University Hospital Geneva; University of Geneva)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Antimicrobial Agents And Chemotherapy , VOL 61

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 14980

Abstract: The outer membrane of Gram-negative bacteria presents an efficient barrier to the permeation of antimicrobial molecules. One strategy pursued to circumvent this obstacle is to hijack transport systems for essential nutrients, such as iron. BAL30072 and MC-1 are two monobactams conjugated to a dihydroxypyridone siderophore that are active against Pseudomonas aeruginosa and Acinetobacter baumannii. Here, we investigated the mechanism of action of these molecules in A. baumannii. We identified two novel TonB-dependent receptors, termed Ab-PiuA and Ab-PirA, that are required for the antimicrobial activity of both agents. Deletion of either piuA or pirA in A. baumannii resulted in 4- to 8-fold-decreased susceptibility, while their overexpression in the heterologous host P. aeruginosa increased susceptibility to the two siderophore-drug conjugates by 4- to 32-fold. The crystal structures of PiuA and PirA from A. baumannii and their orthologues from P. aeruginosa were determined. The structures revealed similar architectures; however, structural differences between PirA and PiuA point to potential differences between their cognate siderophore ligands. Spontaneous mutants, selected upon exposure to BAL30072, harbored frameshift mutations in either the ExbD3 or the TonB3 protein of A. baumannii, forming the cytoplasmic-membrane complex providing the energy for the siderophore translocation process. The results of this study provide insight for the rational design of novel siderophore-drug conjugates against problematic Gram-negative pathogens.

Journal Keywords: Acinetobacter baumannii; Pseudomonas aeruginosa; siderophore-drug receptor

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 29/03/2017 11:31

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)