Targeted therapeutic agent for Streptococcus pneumoniae stereotype 3 infection

ABSTRACT

Streptococcus pneumoniae (Spn) is a Gram-positive bacterial pathogen, which has been a major threat to human health. Spn is the causal agent to the invasive pneumococcal diseases (IPD) and according to CDC, IPD causes 150,000 hospitalizations every year in the United States alone. Additionally, pneumococcal co-infections are a driving force behind the mortality associated with other infectious diseases, such as flu and more recent pandemic outbreak COVID-19. Importantly recent report from WHO confirmed that, Spn is an antimicrobial resistance (AMR) bacterial pathogen, and it is becoming resistant to antibiotic therapies which are widely used to treat Spn infections. Among more than hundred different Spn strains, serotype 3 (Spn3) has unique biological and physical structural challenges such as thick capsular polysaccharide (CPS), high viscosity and mucoid nature, which help Spn3 to escape from host immune responses. The CPS of Spn3 also renders it a highly unresponsive stereotype to the multivalent conjugate vaccine developed against Spn, and thus incidence rates of serotype 3 continue to raise. Because of the unresponsiveness to available pneumococcal conjugate vaccines (PCV) and antibiotics resistance, a novel therapeutic agent is necessary to control the invasive pneumococcal serotype 3 infection. We have identified and cloned the Pn3Pase gene expressed by a Paenibacillus strain. The purified Pn3Pase enzyme degrades the CPS of the Spn3, rendering the bacterium immune-susceptible. We confirmed that recombinantly purified Pn3Pase can degrade the capsule of living Spn3;the unencapsulated Spn3 are not infectious. Also, Spn3 that is unencapsulated by Pn3Pase is efficiently targeted by phagocytosis which also limits the nasopharyngeal colonization in a mouse colonization model. We have also observed that Pn3Pase protects the mice from lethal challenge with Spn3. Pn3Pase is not toxic and repeated administration in mice does not stimulate significant host immune responses against the enzyme. Our results indicate that Pn3Pase serves as an alternative to antibiotics and could effectively make up for vaccine shortcomings, therefore a promising therapeutic agent against Spn3 infections.