**Background:** Streptococcus pneumoniae is a leading cause of community-acquired pneumonia, meningitis, and septicemia, despite vaccination programs. Pneumolysin (PLY) is a 53 kDa cholesterol-dependent cytolysin produced by all pneumococci, which forms pores in eukaryotic cell membranes, leading to cell destruction. PLY also activates inflammatory pathways (NF-κB, MAPK, NLRP3 inflammasome) and contributes to pulmonary edema, cardiovascular events, and immune evasion. Current vaccines cover limited serotypes, and antibiotic resistance is rising, necessitating new therapies targeting PLY. This systematic review evaluates molecules that inhibit PLY as potential treatments.
**Methods:** A systematic search of MEDLINE, Web of Science, and Scopus was conducted for articles published from January 1, 2000, to November 25, 2021, using the terms "pneumolysin" AND "therapeutic". Exclusion criteria included non-English articles, patents, case reports, notes, book chapters, and reviews. Two independent reviewers screened titles, abstracts, and full texts, resolving disagreements by consensus. Methodological quality was assessed using the OHAT framework. Data on molecules, mechanisms, cell lines, animal models, and outcomes were extracted. Due to heterogeneity, meta-analysis was not possible.
**Key Results:** Of 366 initial records, 41 studies met inclusion criteria. The studies were predominantly from China (n=17), Europe (n=10), and the USA (n=9). Fifteen studies used only cell cultures, while 26 used animal models (pneumonia, meningitis, keratitis, atherosclerosis, nasopharyngeal colonization). The molecules were classified into 10 groups: plant-derived compounds (polyphenols, flavonoids, tannins, quinones, phenethylamines, terpenoids), sterols, statins, omega-3 fatty acids, purin-6-ones, thioethers, antibiotics, peptides, cations, and antibodies. Direct inhibitors (e.g., flavonoids, sterols) bind PLY and block oligomerization; indirect inhibitors (e.g., statins, thioethers) prevent PLY effects on host cells; unknown mechanisms apply to some (e.g., cations, certain antibiotics). Key examples: Verbascoside (polyphenol) binds PLY domains 3 and 4, inhibiting oligomerization and reducing TNF-α and IL-1β in mice. Epigallocatechin gallate (EGCG) increased survival by ~40% at 120 h in mice. Quercetin improved survival to 80% vs 60% in controls. β-sitosterol (sterol) provided 70% survival at 5 days in mice. Simvastatin (statin) reduced lung injury and inflammation in mice. Montelukast (thioether) improved survival in mice. DM3 peptide combined with penicillin achieved 100% survival in systemic infection. Anti-PLY antibodies increased survival (10/20 vs 2/20) in mice. Cations (Mg²⁺, Zn²⁺, Ca²⁺) reduced pore formation. The OHAT quality assessment rated most studies as Low or Probably Low risk of bias.
**Clinical Implications:** PLY is a promising therapeutic target for pneumococcal infections. Many molecules reviewed have already been used in humans for other conditions (e.g., statins, montelukast, clarithromycin, quercetin), suggesting potential safety for repurposing. These molecules could serve as adjuncts to antibiotics, particularly in early infection stages, to prevent acute respiratory distress syndrome and invasive disease. However, clinical trials are limited; only 17 of 39 molecules have human trial data. The heterogeneity of studies precludes meta-analysis, and further research is needed to optimize dosing, routes, and combinations. The knowledge network highlights that pore formation, hyperpermeability, and inflammation are key processes targeted. Future studies should focus on clinical translation, especially for molecules with established safety profiles.