TonB-dependent siderophore transporter (TBDR)

TonB-dependent siderophore transporters are essential outer membrane proteins in Gram-negative bacteria that facilitate the active uptake of iron-siderophore complexes from the extracellular environment [1]. Because free iron is extremely scarce within a host due to sequestration by proteins like transferrin, bacteria secrete small molecules called siderophores to scavenge iron; these transporters then recognize and internalize the iron-laden complexes using energy derived from the inner membrane TonB-ExbB-ExbD system [1,3]. In the context of drug development, these transporters are the primary targets for "Trojan horse" antibiotics, most notably Cefiderocol, which features a catechol moiety that mimics natural siderophores [2]. This mechanism allows the antibiotic to bypass traditional resistance pathways, such as porin loss or efflux pump overexpression, by being actively transported into the periplasmic space where it can inhibit cell wall synthesis [2]. These transporters are critical for the survival and virulence of multidrug-resistant pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, and Carbapenem-resistant Enterobacteriaceae [2,3]. Sources: [1] Noinaj et al. (2010) Nature Reviews Microbiology; [2] Zhanel et al. (2019) Drugs; [3] Holden and Bachman (2015) Annals of the American Thoracic Society.

Other names

Ferric-siderophore receptorOuter membrane siderophore transporterTonB-dependent receptorSiderophore-iron transporterIron-siderophore uptake protein

Siderophore-mediated active transport (Trojan horse mechanism) where the drug mimics a ferric-siderophore complex to be actively pulled into the bacterial periplasm via the transporter.