Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model.
PBT2
Streptococcus pneumoniae
antibiotics
antimicrobial resistance
bacterial pathogen
ionophore
multidrug resistance
zinc
zinc intoxication
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
11 01 2022
11 01 2022
Historique:
received:
06
01
2021
revised:
24
09
2021
accepted:
13
12
2021
entrez:
12
1
2022
pubmed:
13
1
2022
medline:
15
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35021083
pii: S2211-1247(21)01706-X
doi: 10.1016/j.celrep.2021.110202
pmc: PMC9084593
mid: NIHMS1771084
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
PBT2 compound
0
Clioquinol
7BHQ856EJ5
Ampicillin
7C782967RD
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
110202Subventions
Organisme : NIAID NIH HHS
ID : R01 AI110618
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI124302
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests C.A.M., A.G.M., M.V.I., and M.J.W. hold an intellectual property interest in this work (PCT/AU2018/051116).
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