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Repurposed Drug Helps Curb Antibiotic-Resistant Pneumonia in Mice

3D computer-generated image of a group of Streptococcus pneumoniae bacteria, based upon scanning electron microscopic (SEM) imagery.
3D computer-generated image of a group of Streptococcus pneumoniae bacteria, based upon scanning electron microscopic (SEM) imagery. Credit: CDC
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A new study has found that the drug fomepizole – already approved by the US Federal Drug Administration (FDA) to treat methanol poisoning – can help to treat antibiotic-resistant pneumonia in mice. The research is published in PLOS Biology.

The challenge of treating pneumococcal infection

Pneumococcal pneumonia, an acute lung infection caused by the bacterium Streptococcus pneumoniae, is responsible for around 150,000 hospitalizations in the US every year and is fatal in 1 in 20 of those infected. S. pneumoniae is the main source of community-acquired pneumonia, where the disease is contracted outside of a hospital setting.

Vaccines against S. pneumoniae are available, though they are not able to protect against all its different strains. This presents a significant problem as some strains are multidrug-resistant i.e., they are resistant to several different antibiotics. Treatment options for infections with these strains are therefore extremely limited.

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S. pneumoniae relies on the breakdown of sugar (glycolysis) and fermentation to generate energy, and the researchers in the current study set out to determine if disrupting this process could help to treat infections with S. pneumoniae.

Overcoming multidrug resistance

The researchers conducted experiments using mice inoculated with a multidrug-resistant S. pneumoniae strain to model pneumonia. They found that fomepizole – a drug that inhibits the enzyme alcohol dehydrogenase and is already FDA-approved to treat suspected methanol poisoning – was effective at blocking the bacteria’s energy production.

Fomepizole treatment also made the bacteria more sensitive to the antibiotic erythromycin when given in combination, reducing the burden of bacteria in the mice’s lungs and preventing the disease from becoming more invasive.

Carlos J. Orihuela, the senior author of the study and professor of microbiology at the University of Alabama, summarized: “Pharmacological targeting of fermentation pathways is a new way to enhance the susceptibility of some bacteria to antimicrobials. Combination treatment of erythromycin and fomepizole, an alcohol dehydrogenase inhibitor, prevented the in vivo dissemination of antibiotic-resistant Streptococcus pneumoniae.”

Nevertheless, additional research in humans is required to determine if this novel drug treatment could be successful in treating patients. This is important as people may present with other complicating factors such as other diseases or conditions, old age and environmental variables that may influence disease outcomes.

“In conclusion, our study, to our knowledge, is the first report demonstrating that drug inhibitor targeting fermentation pathways has potential as an adjuvant to antibiotics,” the researchers write.

Reference: Im H, Pearson ML, Martinez E, Cichos KH et al. Targeting NAD+ regeneration enhances antibiotic susceptibility of Streptococcus pneumoniae during invasive disease. PLoS Biol. 2023;21(3):e3002020. doi: 10.1371/journal.pbio.3002020

This article is a rework of a press release issued by PLOS. Material has been edited for length and content.