Abstract
For many of the most important human bacterial infections, invasive disease severity is fueled by the cell damaging and pro-inflammatory effects of secreted pore-forming toxins (PFTs). Isogenic PFT-knockout mutants, e.g., Staphylococcus aureus lacking α-toxin or Streptococcus pneumoniae deficient in pneumolysin, show attenuation in animal infection models. This knowledge has inspired multi-model investigations of strategies to neutralize PFTs or counteract their toxicity as a novel pharmacological approach to ameliorate disease pathogenesis in clinical disease. Promising examples of small molecule, antibody or nanotherapeutic drug candidates that directly bind and neutralize PFTs, block their oligomerization or membrane receptor interactions, plug establishment membrane pores, or boost host cell resiliency to withstand PFT action have emerged. The present review highlights these new concepts, with a special focus on β-PFTs produced by leading invasive human Gram-positive bacterial pathogens. Such anti-virulence therapies could be applied as an adjunctive therapy to antibiotic-sensitive and -resistant strains alike, and further could be free of deleterious effects that deplete the normal microflora.
Highlights
The rapid emergence of antimicrobial resistant strains of bacteria has exceeded the rate at which anti-bacterial therapies are currently being produced
Studies in a mouse model of sickle cell disease (SCD) suggested that one such drug, Simvastatin, protected host cells from the cytotoxic effects of PLY and other cholesterol-dependent cytolysins (CDCs), including streptolysin O (SLO) and tetanolysin, a finding suggested to reflect the requirement of cholesterol for efficient pore formation and cytotoxicity [113]
After attack by a Pore forming toxins (PFTs), the host cell can respond to this insult through several mechanisms that depend upon the type and concentration of the PFT, as well as the nature of the host cell(s) affected, since both factors differentially influence downstream stress response pathways and signaling events [8]
Summary
The rapid emergence of antimicrobial resistant strains of bacteria has exceeded the rate at which anti-bacterial therapies are currently being produced. While there exists a plethora of virulence mechanisms utilized by pathogenic bacteria to cause disease, the majority produce toxins that induce damage to either gain access to host cells for further proliferation, derive nutrients from host cells, or disrupt host cell immune function to increase their own survival, all of which may lead to host cell death. While the mechanism of PFT pore formation may seem deceptively simple, PFTs can affect intracellular signaling cascades, dependent in part on the membrane structure the are bound to, and can produce a variety of downstream responses, enhancing the pathogenicity of the bacteria that secrete them [5,6,8,9,10,11,12]. These concepts have the potential to become important pharmacological strategies for improving treatment outcomes, used either independently or as an adjunct to classical antibiotic regimens
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