Determinants of susceptibility and tolerance of <i>Streptococcus pneumoniae</i> to hypothiocyanous acid

Infections caused by <i>Streptococcus pneumoniae</i> (<i>Spn</i>, pneumococcus), manifesting as pneumonia, meningitis, and otitis media, represent a leading cause of severe morbidity and mortality globally. Escalating antibiotic resistance and serotype replacement by conjugate vaccines underscore the need for serotype-independent therapies. Hypothiocyanous acid (HOSCN), a reactive oxidant naturally produced by the host innate immune system, is formed through the interaction of hydrogen peroxide, thiocyanate anions (SCN^-), and peroxidase enzymes. HOSCN is produced at mucosal surfaces, including the respiratory epithelium, where it functions as a broad-spectrum oxidative agent. HOSCN has been reported to kill Spn <i>in vitro</i>, but tolerance mechanisms of Spn against HOSCN have also been described. This review synthesizes recent advances in understanding HOSCN's molecular mechanisms of action, tolerance pathways of Spn, and the effects of HOSCN on host-Spn interactions. The article also discusses current limitations and key challenges that must be addressed to translate HOSCN from preclinical promise to clinical application in the management of Spn lung infections. By leveraging an innate microbicidal pathway already active in the healthy lung, HOSCN-based therapeutics could offer rapid, resistance-refractory control of pneumococcal disease.