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

Alexandre Luscher, Lucile Moynie, Pamela Saint Auguste, Dirk Bumann, Lena Mazza, Daniel Pletzer, James H. Naismith, Thilo Köhlera*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)
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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.

Original languageEnglish
Article numbere00097-18
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number6
Early online date25 May 2018
DOIs
Publication statusPublished - Jun 2018

Keywords

  • Pseudomonas aeruginosa
  • Siderophore-drug conjugate
  • TonB-dependent receptor

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