Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model.
Cell Rep, 2022/01/11;38(2):110202.
Brazel EB[1], Tan A[2], Neville SL[2], Iverson AR[3], Udagedara SR[4], Cunningham BA[2], Sikanyika M[5], De Oliveira DMP[6], Keller B[6], Bohlmann L[6], El-Deeb IM[7], Ganio K[2], Eijkelkamp BA[1], McEwan AG[6], von Itzstein M[7], Maher MJ[8], Walker MJ[6], Rosch JW[3], McDevitt CA[9]
Affiliations
PMID: 35021083DOI: 10.1016/j.celrep.2021.110202
Impact factor: 9.995
Abstract
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 ionophore 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol (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 therapeutic modality to break antibiotic resistance in multidrug-resistant S. pneumoniae.
Keywords: PBT2; Streptococcus pneumoniae; antibiotics; antimicrobial resistance; bacterial pathogen; ionophore; multidrug resistance; zinc; zinc intoxication
MeSH terms
Ampicillin; Ampicillin Resistance; Animals; Anti-Bacterial Agents; Clioquinol; Disease Models, Animal; Female; Homeostasis; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pneumonia; Streptococcus pneumoniae; Zinc
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