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

Area of Science:

• Microbiology
• Infectious Diseases
• Biochemistry

Background:

• Anaerobic bacteria cause numerous pulmonary infections, with Streptococcus pneumoniae (Spn) being a primary pathogen responsible for pneumonia, bacteremia/sepsis, and meningitis.
• Maintaining NAD(H) redox balance during fermentation is crucial for Spn's energy production, capsule synthesis, and survival within a host.

Purpose of the Study:

• To investigate the role of NAD(H) redox balance in Spn fermentation on bacterial fitness and susceptibility to antibiotics.
• To explore fermentation enzymes as potential targets for novel antimicrobial drug development.

Main Methods:

• Utilized isogenic mutants lacking key fermentation pathways (lactate, acetyl-CoA, ethanol) and pharmacological inhibitors.
• Assessed the impact of redox balance disruption on Spn's energy generation, capsule production, and in vivo fitness.
• Investigated the effect of blocking alcohol dehydrogenase with 4-methylpyrazole (fomepizole) on multidrug-resistant Spn and in a murine pneumonia model.

Main Results:

• Disruption of NAD(H) redox balance during fermentation significantly impaired Spn's energy generation, capsule production, and in vivo fitness.
• Pathway-specific disruption of redox balance increased Spn's susceptibility to specific antimicrobial classes.
• Fomepizole treatment enhanced erythromycin susceptibility in multidrug-resistant Spn, reduced lung bacterial burden, and prevented invasive disease progression in mice.

Conclusions:

• Fermentation pathways and NAD(H) redox balance are critical for Spn virulence and survival.
• Targeting fermentation enzymes represents a promising de novo strategy for developing new antibiotics against multidrug-resistant pathogens.
• Pharmacological inhibition of alcohol dehydrogenase offers a potential therapeutic approach to combat Spn infections.