Abstract
Streptococcus pneumoniae is an important bacterial pathogen responsible for many serious infections worldwide. Infections are often treated with penicillin antibiotics. This provides a selection pressure for the emergence of resistant strains over time, reducing treatment options and threatening patients. Combining lab evolutionary and comparative genomics approaches, we identify unique loss of function mutations in the Pde1 enzyme that lead to penicillin resistance in the absence of classical resistance determinants. We confirm this effect across clinical isolates and characterize the impact of natural genetic variation on Pde1 function. Characterization of end-stage penicillin resistance genes has, so far, not led to effective mitigations. Here, by characterizing the evolutionary events leading toward resistance, we open different possibilities for interventions against resistant S. pneumoniae.