Scientific article
OA Policy
English

Tonb-dependent receptor repertoire of pseudomonas aeruginosa for uptake of siderophore-drug conjugates

Published inAntimicrobial Agents and Chemotherapy, vol. 62, no. 6, p. e00097-18
Publication date2018
Abstract

The conjugation of siderophores to antimicrobial molecules is an attractive strategy to overcome the low outer membrane permeability of Gram-negative bacteria. In this Trojan horse approach, the transport of drug conjugates is redirected via TonB-dependent receptors (TBDR), which are involved in the uptake of essential nutrients, including iron. Previous reports have demonstrated the involvement of the TBDRs PiuA and PirA from Pseudomonas aeruginosa and their orthologues in Acinetobacter baumannii in the uptake of siderophore-beta-lactam drug conjugates. By in silico screening, we further identified a PiuA orthologue, termed PiuD, present in clinical isolates, including strain LESB58. The piuD gene in LESB58 is located at the same genetic locus as piuA in strain PAO1. PiuD has a similar crystal structure as PiuA and is involved in the transport of the siderophore-drug conjugates BAL30072, MC-1, and cefiderocol in strain LESB58. To screen for additional siderophore-drug uptake systems, we overexpressed 28 of the 34 TBDRs of strain PAO1 and identified PfuA, OptE, OptJ, and the pyochelin receptor FptA as novel TBDRs conferring increased susceptibility to siderophore-drug conjugates. The existence of a TBDR repertoire in P. aeruginosa able to transport siderophore-drug molecules potentially decreases the likelihood of resistance emergence during therapy.

Keywords
  • Anti-Bacterial Agents/metabolism
  • Bacterial Outer Membrane Proteins/genetics/metabolism
  • Bacterial Proteins/genetics/metabolism
  • Biological Transport/drug effects
  • Carrier Proteins/genetics/metabolism
  • Cell Membrane Permeability/drug effects
  • Cephalosporins/metabolism
  • Membrane Proteins/genetics/metabolism
  • Monobactams/metabolism
  • Pseudomonas aeruginosa/genetics/metabolism
  • Siderophores/metabolism
  • Thiazoles/metabolism
  • Beta-Lactams/metabolism
Citation (ISO format)
LUSCHER, Alexandre et al. Tonb-dependent receptor repertoire of pseudomonas aeruginosa for uptake of siderophore-drug conjugates. In: Antimicrobial Agents and Chemotherapy, 2018, vol. 62, n° 6, p. e00097–18. doi: 10.1128/AAC.00097-18
Main files (1)
Article (Published version)
Secondary files (1)
Identifiers
Journal ISSN0066-4804
228views
125downloads

Technical informations

Creation28/10/2020 11:49:00
First validation28/10/2020 11:49:00
Update time08/11/2024 08:29:36
Status update08/11/2024 08:29:36
Last indexation08/11/2024 08:33:54
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack