biostudies-literatureBrazel EBNIAID NIH HHSNational Health and Medical Research CouncilNational Institutes of HealthAustralian Research Council110202https://www.ebi.ac.uk/biostudies/studies/S-EPMC9084593biostudies-literatureUnknown38(2)Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multidrug-resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection, including zinc stress. Here, we characterize the impact of zinc intoxication on S. pneumoniae, observing disruptions in central carbon metabolism, lipid biogenesis, and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU indicates a sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, renders S. pneumoniae highly susceptible to β-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human-use ionophorCell reportsDysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model.PMC908459311761801RO1AI1106181122582DP1701021021U01AI1243021142695U01 AI1243021071659108078411941301140554FT180100397R01 AI110618FT170100006McEwan AGSikanyika MRosch JWWalker MJvon Itzstein MMcDevitt CAUdagedara SRMaher MJTan ABohlmann LKeller BDe Oliveira DMPBrazel EBNeville SLGanio KIverson AREl-Deeb IMEijkelkamp BACunningham BAfalseDysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model.Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multidrug-resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection, including zinc stress. Here, we characterize the impact of zinc intoxication on S. pneumoniae, observing disruptions in central carbon metabolism, lipid biogenesis, and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU indicates a sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, renders S. pneumoniae highly susceptible to β-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human-use ionophor2022-01-01T00:00:00Z2022 Jan2026-05-30T15:26:37.18Z2025-04-04T10:02:02.226ZS-EPMC90845933502108310.1016/j.celrep.2021.110202