Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia despite widespread vaccination programs. This has been attributed to a rise in drug-resistant strains, with ~40% of all clinical disease isolates penicillin-resistant, and the capacity to escape vaccine prophylaxis due to capsule-switching. During infection, the innate immune response uses multiple insults against invading pathogens to control infection, including chemical stress as mediated by niche-specific modulation of zinc abundance. Here, we characterised how S. pneumoniae resists increased zinc stress and identified a single efflux pathway encoded by czcD. Disruption of czcD rendered S. pneumoniae hypersusceptible to zinc, with metabolomic profiling revealing impacts in central carbon metabolism, lipid biogenesis and peptidoglycan biosynthesis. Structural and biochemical characterisation of a pivotal metal-dependent peptidoglycan biosynthetic enzyme GlmU showed that zinc bound to the protein and impaired its essential acetyltransferase activity. Consistent with an impact in peptidoglycan biosynthesis, zinc stress rendered the ΔczcD strain highly susceptible to β-lactam antibiotics. However, zinc did not alter antibiotic sensitivity in the wild-type strain due to the protection provided by CzcD. To defeat zinc homeostasis, we used a metal-permeating ionophore. We investigated PBT2, a safe-for-human use ionophore, and showed that it could render drug resistant S. pneumoniae strains sensitive to β-lactams and other antibiotics. Using an invasive ampicillin-resistant S. pneumoniae strain, we successfully demonstrated the efficacy of PBT2+ampicillin for the treatment of in vivo murine lung infection. Collectively, these findings further elucidate the molecular basis of zinc toxicity in S. pneumoniae and show how this provides a pathway for development of a novel treatment modality that breaks antibiotic resistance in multidrug-resistant strains.