Abstract
Streptococcus pneumoniae is a major human pathogen responsible for millions of deaths worldwide from pneumonia, meningitis and bacteraemia. There is an urgent need for new anti-pneumococcal strategies with antimicrobial resistance increasing globally. One strategy is to target the bacterium’s antioxidant defences to render the bacteria more susceptible to oxidants produced by the immune system. We have shown that S. pneumoniae is unusually tolerant to hypothiocyanous acid (HOSCN), which is generated by host peroxidases at sites of colonisation and infection from the hydrogen peroxide produced by the bacteria themselves. We identified a novel HOSCN reductase enzyme (Har) as a crucial defence mechanism against HOSCN in these bacteria. Here, we report kinetic and structural studies of Har. Furthermore, we demonstrate in mouse models of pneumococcal infection that Har is critical for pneumococcal colonisation of the nasopharynx and invasion of the host. In summary, this work highlights that targeting the ability of S. pneumoniae to tolerate HOSCN via Har may provide a new therapeutic approach to treat this pathogen.