Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model

This study reports on the co-administration of a zinc ionophore (PBT-2) and ampicillin to break antibiotic resistance of Streptococcus pneumoniae in a murine pneumonia model. The molecular mechanism for this heightened antimicrobial activity was identified through transcriptomic and metabolomic analyses of a wild type strain and a zinc efflux mutant to identify cellular targets of zinc intoxication. This revealed that zinc intoxication induces numerous cellular disruptions, which when combined with frontline antibiotics, can break antibiotic resistance and potentially preclude further resistance from emerging. Purified RNA from four biological replicates of untreated S. pneumoniae D39, D39 treated with 100 µM zinc and D39 ∆czcD treated with 100 µM zinc were pooled for RNA sequencing. Data were used to compare gene expression in the untreated cells to the WT treated cells and the ∆czcD treated cells.