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 Vol. 21; no. 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:	Journal Article
Language:	English
Published:	United States Public Library of Science 16-03-2023 Public Library of Science (PLoS)
Subjects:	Alcohol Alcohol dehydrogenase Anaerobic bacteria Analysis Animals Anti-Bacterial Agents - pharmacology Anti-Bacterial Agents - therapeutic use Antibiotics Antibodies Bacteremia Bacteria Bacterial infections Biocompatibility Biology and Life Sciences Dehydrogenases Disease Disease susceptibility Drug resistance Erythromycin Erythromycin - pharmacology Ethanol Fermentation Ingestion Lung Lungs Medicine and Health Sciences Meningitis Metabolism Mice Multidrug resistance Mutation NAD NAD (Coenzyme) Pathogens Physical Sciences Physiology Pneumonia Regeneration (Biology) Sepsis Statistical significance Streptococcus infections Streptococcus pneumoniae Vaccines Virulence United States
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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1545-7885 1544-9173 1545-7885
DOI:	10.1371/journal.pbio.3002020