Targeting StxB-mediated intracellular trafficking as a pharmacological strategy for anti-virulence intervention

Shiga toxin (Stx) is a prototypical bacterial toxin responsible for severe diseases such as hemorrhagic colitis and hemolytic uremic syndrome (HUS). Despite extensive research efforts, therapeutic options remain limited, and no approved strategy directly targets its pathogenic mechanism. Shiga toxin belongs to the AB₅ family and consists of a catalytically active A subunit (StxA) and a pentameric B subunit (StxB). Importantly, its pathogenicity depends not simply on the enzymatic activity of StxA but critically on the host cell entry and intracellular trafficking mediated by the StxB. Through multivalent binding to the Gb3 receptor, StxB reorganizes membrane microdomains and initiates endocytosis. A substantial fraction of internalized toxin escapes lysosomal degradation and instead exploits the Golgi-endoplasmic reticulum (ER) retrograde transport pathway to enable cytosolic delivery of StxA. This sequence of events constitutes a rate-limiting determinant of toxin pathogenicity and demonstrates that StxB actively orchestrates host intracellular trafficking networks rather than serving merely as a receptor-binding component. In this review, we integrate molecular and biophysical mechanisms of StxB-mediated intracellular trafficking and comparatively evaluate the druggability of each trafficking step. In particular, we reinterpret approaches such as inhibition of toxin binding, disruption of membrane microdomains, blockade of endocytosis, and inhibition of Golgi-ER retrograde transport from the perspective of anti-virulence therapy. We propose that selective modulation of StxB-dependent trafficking bottlenecks represents a conceptually novel therapeutic strategy that can attenuate host damage while reducing the risk of resistance development.