TonB-dependent outer membrane transporter (TBDT)

TonB-dependent outer membrane transporters (TBDTs) are specialized proteins in Gram-negative bacteria that facilitate the active uptake of essential nutrients, most notably iron-siderophore complexes (UniProt, 2024). Because free iron is extremely scarce in the human host due to nutritional immunity, bacteria rely on these transporters to scavenge iron for survival and pathogenesis (Nature Reviews Microbiology, 2021). These transporters consist of a 22-stranded beta-barrel plugged by a globular N-terminal domain, and their activity is energized by the inner membrane proton motive force via the TonB-ExbB-ExbD complex (PubMed, PMID: 31273324). In drug development, TBDTs are exploited through the "Trojan horse" strategy, where an antibiotic is chemically linked to a siderophore to bypass the outer membrane permeability barrier (StatPearls, 2023). Cefiderocol is a clinically approved siderophore-cephalosporin conjugate that utilizes this mechanism to treat multi-drug resistant infections caused by pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii (FDA, 2019). While highly effective, therapeutic challenges include the potential for bacteria to develop resistance by mutating or downregulating these specific transport channels (Journal of Antimicrobial Chemotherapy, 2022).

Other names

Bacterial outer membrane iron transporterTonB-dependent receptorSiderophore receptorOuter membrane receptor proteinIron-regulated outer membrane proteinIROMP

Siderophore-mediated active transport (Trojan horse mechanism) where antibiotics are conjugated to siderophore-like moieties to facilitate active entry into the bacterial periplasm via the transporter.