Targeting NAD+ regeneration enhances antibiotic susceptibility of Streptococcus pneumoniae during invasive disease

Anaerobic bacteria are responsible for half of all pulmonary infections. One such pathogen is Streptococcus pneumoniae (Spn), a leading cause of community-acquired pneumonia, bacteremia/sepsis, and meningitis. Using a panel of isogenic mutants deficient in lactate, acetyl-CoA, and ethanol fermentati...

Full description

Saved in:
Bibliographic Details
Published in:PLoS biology 2023-03, Vol.21 (3), p.e3002020
Main Authors: Im, Hansol, Pearson, Madison L, Martinez, Eriel, Cichos, Kyle H, Song, Xiuhong, Kruckow, Katherine L, Andrews, Rachel M, Ghanem, Elie S, Orihuela, Carlos J
Format: Article
Language:English
Subjects:
Alcohol
Alcohol dehydrogenase
Anaerobic bacteria
Animals
Anti-Bacterial Agents - pharmacology
Anti-Bacterial Agents - therapeutic use
Antibiotics
Antibodies
Bacteremia
Bacteria
Bacterial infections
Biocompatibility
Biology and Life Sciences
Dehydrogenases
Disease
Drug resistance
Erythromycin
Erythromycin - pharmacology
Ethanol
Fermentation
Ingestion
Lung
Lungs
Medicine and Health Sciences
Meningitis
Metabolism
Mice
Multidrug resistance
Mutation
NAD
Pathogens
Physical Sciences
Physiology
Pneumonia
Sepsis
Statistical significance
Streptococcus infections
Streptococcus pneumoniae
Vaccines
Virulence
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Anaerobic bacteria are responsible for half of all pulmonary infections. One such pathogen is Streptococcus pneumoniae (Spn), a leading cause of community-acquired pneumonia, bacteremia/sepsis, and meningitis. Using a panel of isogenic mutants deficient in lactate, acetyl-CoA, and ethanol fermentation, as well as pharmacological inhibition, we observed that NAD(H) redox balance during fermentation was vital for Spn energy generation, capsule production, and in vivo fitness. Redox balance disruption in fermentation pathway-specific fashion substantially enhanced susceptibility to killing in antimicrobial class-specific manner. Blocking of alcohol dehydrogenase activity with 4-methylpyrazole (fomepizole), an FDA-approved drug used as an antidote for toxic alcohol ingestion, enhanced susceptibility of multidrug-resistant Spn to erythromycin and reduced bacterial burden in the lungs of mice with pneumonia and prevented the development of invasive disease. Our results indicate fermentation enzymes are de novo targets for antibiotic development and a novel strategy to combat multidrug-resistant pathogens.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3002020