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Diphtheria toxin (DT) is the archetype for bacterial exotoxins implicated in human diseases and has played a central role in defining the field of toxinology since its discovery in 1888. Despite being one of the most extensively characterized bacterial toxins, the origins and evolutionary adaptation of DT to human hosts remain unknown. Here, we determined the first high-resolution structures of DT homologs outside of the Corynebacterium genus. DT homologs from Streptomyces albireticuli (17% identity to DT) and Seinonella peptonophila (20% identity to DT), despite showing no toxicity toward human cells, display significant structural similarities to DT sharing both the overall Y-shaped architecture of DT as well as the individual folds of each domain. Through a systematic investigation of individual domains, we show that the functional determinants of host range extend beyond an inability to bind cellular receptors; major differences in pH-induced pore-formation and cytosolic release further dictate the delivery of toxic catalytic moieties into cells, thus providing multiple mechanisms for a conserved structural fold to adapt to different hosts. Our work provides structural insights into the expanding DT family of toxins, and highlights key transitions required for host adaptation. Toxic proteins are responsible for the disease symptoms accompanying bacterial infections. Sugiman-Marangos et al. report crystal structures of two diphtheria toxin homologs, therefore providing structural insights into this family of toxins and the evolutionary adaptation of these toxins to human hosts. [ABSTRACT FROM AUTHOR]

The article presents a study which adopted the strategy by diphtheria toxin to enter into the endolysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and lysosomal hydrolase tripeptidyl peptidase-1 (TPP1) to improve the effectiveness of enzyme replacement therapy as treatment of lysosomal storage diseases (LSD). Based on the results, chimeric TPP1 binds strongly to target cells.

Diphtheria toxin (DT), produced by Corynebacterium diphtheria, is the causative agent of diphtheria and one of the most potent protein toxins known; however, it has an unclear evolutionary history. Here, we report the discovery of a DT‐like gene family in several bacterial lineages outside of Corynebacterium, including Austwickia and Streptomyces. These DT‐like genes form sister lineages in the DT phylogeny and conserve key DT features including catalytic and translocation motifs, but possess divergent receptor‐binding domains. DT‐like genes are not associated with corynephage, but have undergone lateral transfer through a separate mechanism. The discovery of the first non‐Corynebacterium homologs of DT sheds light on its evolutionary origin and highlights novelties that may have resulted in the emergence of DT targeting humans. [ABSTRACT FROM AUTHOR]

Despite enormous efforts, achieving efficacious levels of proteins inside mammalian cells remains one of the greatest challenges in biologics-based drug discovery and development. The inability of proteins to readily cross biological membranes precludes access to the wealth of intracellular targets and applications that lie within mammalian cells. Existing methods of delivery commonly suffer from an inability to target specific cells and tissues, poor endosomal escape, and limited in vivo efficacy. The aim of the present commentary is to highlight the potential of certain classes of bacterial toxins, which naturally deliver a large protein into the cytosolic compartment of target cells after binding a host cell-surface receptor with high affinity, as robust protein delivery platforms. We review the progress made in recent years toward demonstrating the utility of these systems at delivering a wide variety of protein cargo, with special attention paid to three distinct toxin-based platforms. We contend that with recent advances in protein deimmunization strategies, bacterial toxins are poised to introduce biologics into the inner sanctum of cells and treat a wealth of heretofore untreatable diseases with a new generation of therapeutics. [ABSTRACT FROM AUTHOR]