Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multi-drug resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection, including zinc stress mediated by localized changes in the abundance of this metal ion. Here, we characterized the impact of zinc intoxication on S. pneumoniae, revealing disruptions in central carbon metabolism, lipid biogenesis and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU revealed an exquisite sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, rendered S. pneumoniae highly susceptible to b-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human use ionophore PBT2. PBT2 rendered wild-type S. pneumoniae strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2+ampicillin treatment. These findings present a novel therapeutic modality to break resistance of drug-resistant S. pneumoniae.