Fomepizole, an FDA-approved drug to treat methanol poisoning, and erythromycin could offer a novel therapeutic option to fight drug-resistant S. pneumoniae.
A new target against pneumonia due to infections by Streptococcus pneumoniae could interfere with the bacteria’s fermentation metabolism, according to a recent study. Fomepizole could offer a novel therapeutic option to fight drug-resistant S. pneumoniae.
“Fomepizole, or other drugs that inhibit bacterial metabolism, have potential to dramatically increase the efficacy of erythromycin and other antibiotics, respectively, in vivo,” Carlos Orihuela, PhD, professor and interim chair of the Department of Microbiology at the University of Alabama at Birmingham, said in a statement.
Investigators showed that giving an FDA-approved drug to treat methanol poisoning in combination with the antibiotic erythromycin significantly reduced the virus in mice infected with virulent, multi-drug resistant S. pneumoniae.
The combination therapy reduced the bacterial burden in the lungs by approximately 95% and in the spleen and heart by 100- and 700-fold, respectively.
Investigators also reported that fomepizole alone or erythromycin alone had no effect.
Fomepizole disrupts the activity of the enzyme alcohol dehydrogenase in the bacteria.
Investigators infected the mice intratracheally with the multidrug-resistant clinical isolate, S. pneumoniae serotype 35B strain 162–5678, which has high resistance to erythromycin.
After 18 hours of infection, the mice were given a single injection of erythromycin with or without fomepizole.
“We also evaluated whether fomepizole treatment impacted the antibiotic susceptibility of other anaerobic gram-positive bacteria, including other streptococcal pathogens, including Streptococcus pyogenes, Streptococcus agalactiae, and Enterococcus faecium, to erythromycin or gentamicin,” Orihuela said in the statement. “We observed from 2-fold to 8-fold decreased minimal inhibitory concentration with fomepizole in most cases, including E. faecium.”
S. pneumoniae produces energy through fermentation, in which pyruvate is converted to lactate, acetate, ethanol, and glycolysis, which needs nicotinamide adenine dinucleotide and hydrogen to regenerate NAD+.
The maintenance of NAD+ pool, which is necessary for redox balance, is essential for sustained energy production, bacterial growth, and survival, according to the statement.
Investigators made S. pneumoniae mutants in 5 enzymes involved in fermentation and NAD+ production.
They found that the mutants generally had impaired metabolism, and 2 of the mutants, 1 for lactate dehydrogenase and 1 for alcohol dehydrogenase, had significant decreases in intracellular pool of ATP, an energy molecule in living cells. They found that the other 3 also had decreases but were more modest.
Additionally, investigators noticed that the NAD+/NADH redox imbalances in the mutations interfered with the production of S. pneumoniae virulence factors and colonization in the mouse nasopharynx. Some of these mutations were susceptible to antibiotics, within the 3 tested antibiotics including erythromycin, and interfered with protein synthesis. Two of the antibiotics disrupted the cell wall synthesis and 1 targeted DNA transcription.
Treating the wildtype S. pneumoniae without a mutation in alcohol dehydrogenase or the other enzymes with fomepizole alone caused redox imbalances. In vitro tests showed that using fomepizole to treat S. pneumoniae enhanced its susceptibility to antibiotics, including a 4-fold decrease in the minimal inhibitory concentrations of erythromycin and gentamicin.
Fomepizole helps overcome antibiotic-resistant pneumonia in mice. News release. EurekAlert. March 29, 2023. Accessed March 30, 2023. https://www.eurekalert.org/news-releases/984375