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Alnustone inhibits Streptococcus pneumoniae virulence by targeting pneumolysin and sortase A
Can Zhang1, Yanhong Deng1, Xinyu Wang1
1State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
Abstract:
Streptococcus pneumoniae (S. pneumoniae) is a major Gram-positive opportunistic pathogen that causes pneumonia, bacteremia, and other fatal infections. This bacterium is responsible for more deaths than any other single pathogen in the world. Inexplicably, these symptoms persist despite the administration of effective antibiotics. Targeting pneumolysin (PLY) and sortase A (SrtA), the major virulence factors of S. pneumoniae, this study uncovered a novel resistance mechanism to S. pneumoniae infection. Using protein phenotype assays, we determined that the small molecule inhibitor alnustone is a potent drug that inhibits both PLY and SrtA. As essential virulence factors of S. pneumoniae, PLY and SrtA play a significant role in the occurrence of infection. Furthermore, evaluation using PLY-mediated hemolysis assay demonstrated alunstone had the potential to interrupt the haemolytic activity of PLY with treatment alunstone (4 μg/ml). Co-incubation of S. pneumoniae D39 SrtA with small-molecule inhibitors decreases cell wall-bound Nan A (pneumococcal-anchored surface protein SrtA), inhibits biofilm formation, and reduces biomass significantly. The protective effect of invasive pneumococcal disease (IPD) on murine S. pneumoniae was demonstrated further. Our study proposes a comprehensive bacteriostatic mechanism for S. pneumoniae and highlights the significant translational potential of targeting both PLY and SrtA to prevent pneumococcal infections. Our findings indicate that the antibacterial strategy of directly targeting PLY and SrtA with alnustone is a promising treatment option for S. pneumoniae and that alnustone is a potent inhibitor of PLY and SrtA.
Insights
Alnustone, a novel small molecule, effectively inhibits Streptococcus pneumoniae virulence factors pneumolysin (PLY) and sortase A (SrtA). This discovery offers a promising new strategy to combat antibiotic-resistant pneumococcal infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- * *Streptococcus pneumoniae* (S. pneumoniae) is a leading cause of fatal bacterial infections worldwide.
- * Antibiotic resistance in S. pneumoniae necessitates novel therapeutic strategies.
- * Pneumolysin (PLY) and sortase A (SrtA) are key virulence factors contributing to S. pneumoniae pathogenesis.
Purpose of the Study:
- * To identify and characterize novel inhibitors targeting S. pneumoniae virulence factors PLY and SrtA.
- * To elucidate the mechanism of action of the small molecule alnustone against S. pneumoniae.
- * To evaluate the therapeutic potential of alnustone in preventing and treating S. pneumoniae infections.
Main Methods:
- * Protein phenotype assays were employed to assess alnustone's inhibitory activity against PLY and SrtA.
- * PLY-mediated hemolysis assays were conducted to evaluate alnustone's effect on PLY's hemolytic activity.
- * Assays involving co-incubation of S. pneumoniae with alnustone were used to assess effects on cell wall-bound proteins, biofilm formation, and biomass.
- * In vivo murine models were utilized to demonstrate the protective efficacy against invasive pneumococcal disease.
Main Results:
- * Alnustone was identified as a potent inhibitor of both pneumolysin (PLY) and sortase A (SrtA).
- * Alnustone demonstrated the ability to interrupt the hemolytic activity of PLY.
- * Treatment with alnustone reduced cell wall-bound Nan A, inhibited biofilm formation, and decreased biomass in S. pneumoniae.
- * Alnustone conferred a protective effect against invasive pneumococcal disease in a murine model.
Conclusions:
- * Alnustone represents a promising therapeutic agent for combating *Streptococcus pneumoniae* infections.
- * Targeting both PLY and SrtA with alnustone offers a novel bacteriostatic strategy against S. pneumoniae.
- * The findings highlight the significant translational potential of alnustone in preventing and treating pneumococcal diseases.
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