Pentamidine inhibition of streptopain attenuates Streptococcus pyogenes virulence

The obligate human pathogen Group A Streptococcus (GAS; Streptococcus pyogenes) carries high morbidity and mortality, primarily in impoverished or resource-poor regions. The failure rate of monotherapy with conventional antibiotics is high, and invasive infections by this bacterium frequently require extensive supportive care and surgical intervention. Thus, it is important to find new compounds with adjunctive therapeutic benefits. The conserved secreted protease streptopain (Streptococcal pyrogenic exotoxin B; SpeB) directly contributes to disease pathogenesis by inducing pathological inflammation, degrading tissue, and promoting the evasion of antimicrobial host defense proteins. This study screened 400 diverse off-patent drug and drug-like compounds for inhibitors of streptopain proteolysis. Lead compounds were tested for activity at lower concentrations and anti-virulence activities during in vitro infection. Significant inhibition of streptopain was seen for pentamidine, an anti-protozoal drug approved for the treatment of pneumocystis pneumonia, leishmaniasis, and trypanosomiasis. Streptopain inhibition rendered GAS susceptible to killing by human innate immune cells. These studies identify unexploited molecules as new starting points for drug discovery and a potential for repurposing existing drugs for the treatment of infections by GAS.