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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.
