Dysregulation 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...

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Published in:Cell reports (Cambridge) 2022-01, Vol.38 (2), p.110202-110202, Article 110202
Main Authors: Brazel, Erin B., Tan, Aimee, Neville, Stephanie L., Iverson, Amy R., Udagedara, Saumya R., Cunningham, Bliss A., Sikanyika, Mwilye, De Oliveira, David M.P., Keller, Bernhard, Bohlmann, Lisa, El-Deeb, Ibrahim M., Ganio, Katherine, Eijkelkamp, Bart A., McEwan, Alastair G., von Itzstein, Mark, Maher, Megan J., Walker, Mark J., Rosch, Jason W., McDevitt, Christopher A.
Format: Article
Language:English
Subjects:
Ampicillin - pharmacology
Ampicillin Resistance - genetics
Ampicillin Resistance - physiology
Animals
Anti-Bacterial Agents - pharmacology
antibiotics
antimicrobial resistance
bacterial pathogen
Clioquinol - analogs & derivatives
Clioquinol - pharmacology
Disease Models, Animal
Female
Homeostasis
ionophore
Mice
Mice, Inbred BALB C
Microbial Sensitivity Tests
multidrug resistance
PBT2
Pneumonia
Streptococcus pneumoniae
Streptococcus pneumoniae - metabolism
zinc
Zinc - metabolism
zinc intoxication
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Summary: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. [Display omitted] •Zinc can impair the activity of the peptidoglycan biosynthetic enzyme GlmU•The zinc ionophore PBT2 overwhelms S. pneumoniae zinc resistance mechanisms•PBT2-mediated zinc intoxication breaks resistance to multiple antibiotic classes•PBT2 rescues ampicillin efficacy during drug-resistant S. pneumoniae lung infection Antibiotic resistance is a growing threat to treatment of pneumonia caused by Streptococcus pneumoniae. Brazel et al. show how zinc can be used to break bacterial antibiotic resistance. They repurpose the safe-for-human-use zinc transporting ionophore, 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol (PBT2), to break bacterial drug resistance during lung infection and restore the efficacy of ampicillin treatment.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.110202