Pore-forming toxins. These proteins/peptides are synthesized by one cell and secreted for insertion into the membrane of another cell where they form transmembrane pores. They may exert their toxic effects by allowing the free flow of electrolytes and other small molecules across the membrane, or they may allow entry into the target cell cytoplasm of a toxin protein that ultimately kills the cell. Both protein (large) and ribosomally synthesized peptide (small) toxins are included in this category. Bacterial pathogens have developed countermeasures to resist these agents by reducing the negative charge of membranes, by active efflux, by proteolytic degradation, and by binding the cationic peptides to capsular polysaccharides (Llobet et al., 2008). Membrane lateral heterogeneity, thickness, and fluidity can influence the pore forming process (Rojko and Anderluh 2015). Some antimicrobial peptides (AMPs) exert intracellular inhibitory activities as a primary or supportive mechanism to achieve efficient killing. Le et al. 2017 reviewed major intracellular targeting activities reported for AMPs which include nucleic acid, cell wall, lipopolysaccharide and protein biosyntheses, protein folding, protease activities and cell division. The interaction of pore-forming toxins with lipid membranes not only causes permeabilization but also causes extensive plasma membrane reorganization. This includes lateral rearrangement and deformation of the lipid membrane, which can lead to the disruption of target cell function and finally death (Kulma and Anderluh 2021).

Pore-forming toxins (PFTs) are the most common bacterial cytotoxic proteins and are required for virulence in a large number of important pathogens, including Streptococcus pneumoniae, group A and B streptococci, Staphylococcus aureus, Escherichia coli, and Mycobacterium tuberculosis. PFTs generally disrupt host cell membranes, but they can have additional effects independent of pore formation. Substantial effort has been devoted to understanding the molecular mechanisms underlying the functions of certain model PFTs. Likewise, specific host pathways mediating survival and immune responses in the face of toxin-mediated cellular damage have been delineated. However, less is known about the overall functions of PFTs during infection in vivo. This review focuses on common themes in the area of PFT biology, with an emphasis on studies addressing the roles of PFTs in in vivo and ex vivo models of colonization or infection. Common functions of PFTs include disruption of epithelial barrier function and evasion of host immune responses, which contribute to bacterial growth and spreading. The widespread nature of PFTs make this group of toxins an attractive target for the development of new virulence-targeted therapies that may have broad activity against human pathogens. The 3D structures of many bacterial pore-forming toxins have been reviewed (Gupta et al. 2023).