Molecular insights into ferric-siderophore transport by the putative TonB-dependent transporter in <i>Mycobacterium tuberculosis</i>

Iron acquisition is critical to the virulence of Mycobacterium tuberculosis ( Mtb ), the causative agent of tuberculosis. To acquire iron within the host, Mtb secretes siderophores that chelate iron with high affinity. Siderophores scavenge iron from host cells using TonB-dependent transporters like FecA. We investigated molecular mechanisms of FecA-mediated ferric-siderophore transport in Mtb . Molecular docking and molecular dynamics simulations revealed a series of interactions between ferric siderophores and FecA. The initial binding occurs at a pocket located on the extracellular surface of FecA. The ligand then migrates deeper through the transport tunnel to a subsequent binding site, aided by conformational changes in FecA that expand the tunnel diameter. We observed the key roles of precise positioning of extracellular loops in the outer membrane barrel and plug domains in the optimal ligand binding and transport. Transport of ferric-siderophore complex into Mtb follows an induced fit model, with ligand interaction eliciting 2-10 Å shifts in the barrel and plug regions. By revealing the conformational dynamics enabling iron import, these findings provide molecular-level insights into a metal ion uptake mechanism in Mtb . Iron acquisition is essential for Mtb pathogenesis, so this work may inform novel therapeutic strategies that disrupt siderophore uptake pathways.