Abstract
SUMMARYStreptococcus pneumoniae (S. pneumoniae) is a major human pathogen that can cause severe diseases such as meningitis and bacteremia. β-lactam antibiotics are the most essential antimicrobial agents for treating S. pneumoniae infections, but the resistance has become a significant challenge in clinical therapy. Analyses reveal notable regional disparities in the prevalence of β-lactam resistance in S. pneumoniae. The use of pneumococcal conjugate vaccines effectively reduces the spread of highly resistant clones, indirectly improving resistance patterns. Interestingly, resistance is inversely correlated with bacterial invasiveness, suggesting mutual selective pressures. Additionally, the COVID-19 pandemic may have influenced the evolution of S. pneumoniae resistance by altering host immune states and healthcare resource allocation. Immunocompromised patients face a higher risk of invasive pneumococcal disease, driving increased antimicrobial use that fuels the rise of resistance. Beyond the single-molecular mechanism, the resistance gene acquisition order plays a critical role in the successful resistance evolution. Analyzing the dynamic principles and key nodes involved in the evolution of drug resistance could offer novel insights for developing precise antibacterial treatment strategies. Current research efforts focus on the development of novel antibiotics, antimicrobial peptides, lysins, and other innovative therapeutic agents. Artificial intelligence shows immense potential in the screening of antimicrobial drugs and the prediction of resistance mechanisms. This review synthesizes recent advances in the epidemiology, molecular mechanisms, and management of β-lactam resistance in S. pneumoniae, with the aim of informing evidence-based antimicrobial stewardship and accelerating the development of innovative therapeutics to combat this evolving public health threat.