TonB-dependent receptor (TBDT) (TBDT)

TonB-dependent receptors (TBDTs) are a family of specialized outer membrane proteins in Gram-negative bacteria that facilitate the active transport of essential nutrients, most notably iron-siderophore complexes, across the outer membrane [Wikipedia, 2024; Chemical Reviews, 2021; Frontiers in Cellular and Infection Microbiology, 2021]. These transporters are energy-dependent, utilizing the TonB-ExbB-ExbD complex in the inner membrane to drive the translocation of large or scarce substrates into the periplasm [Chemical Reviews, 2021; PubMed, 1999]. Because iron is a critical limiting factor for bacterial growth within a host, these receptors are highly expressed during infection as part of the bacterial response to nutritional immunity [PMC, 2019; Frontiers in Cellular and Infection Microbiology, 2021]. This biological necessity is exploited by Trojan horse antibiotics, such as cefiderocol, which are conjugated to siderophore-like moieties [Clinical Infectious Diseases, 2019; Patsnap Synapse, 2024; PMC, 2019]. These drugs bind to TBDTs and are actively imported into the bacterial cell, allowing them to bypass common resistance mechanisms like porin downregulation and efflux pump overexpression [Clinical Infectious Diseases, 2019; PMC, 2022; PMC, 2021]. This strategy allows the antibiotics to achieve high periplasmic concentrations even in multidrug-resistant strains, making TBDTs vital targets for the development of novel therapeutics against challenging Gram-negative pathogens [PMC, 2018; Antimicrobial Agents and Chemotherapy, 2012; PMC, 2019].

Other names

Gram-negative bacterial siderophore-dependent iron transporterSiderophore receptorOuter membrane iron transporterLigand-gated porinTonB-dependent transporterFerric siderophore receptor

Active transport of siderophore-drug conjugates across the outer membrane via a Trojan horse mechanism, bypassing porin-mediated resistance [Clinical Infectious Diseases, 2019; PMC, 2022].