The role of phosphodiesterase in the regulation of <i>Streptococcus pneumoniae </i>drug sensitivity and the therapeutic effect of its inhibitors in mice

The emergence of drug-resistant Streptococcus pneumoniae has become a global health challenge, particularly as a major causative agent of community-acquired pneumonia. Cyclic dimeric adenosine monophosphate (c-di-AMP), a pivotal bacterial second messenger, is known to regulate key physiological processes such as drug resistance in multiple streptococci species. However, its precise role in S. pneumoniae drug resistance remains unclear. This study found that pde1 and pde2, encoding phosphodiesterases (PDEs) of c-di-AMP, regulated morphology, growth and drug sensitivity of S. pneumoniae. Mutation of pde2 significantly increased drug sensitivity to several antibiotics, despite only minor changes in c-di-AMP levels and inconsistent expression shifts in resistance-related genes. Further, a clinical isolate with pde2 mutant showed a higher c-di-AMP level and was more sensitive to several antibiotics, and the mutant PDE2 from S. pneumoniae clinical strain showed reduced phosphodiesterase activity. Moreover, sildenafil, an FDA-approved PDE inhibitor, increased drug sensitivity of clinical resistant S. pneumoniae in vitro, and effectively suppressed bacterial growth and the inflammatory response in mice infected with resistant S. pneumoniae. infected mice. These results suggested that PDE2 could be used as a drug target against resistant S. pneumoniae.