An international team including Australian researchers has found the key to making existing frontline antibiotics work again against the deadly pneumonia-causing bacteria Streptococcus pneumoniae.
The study, published in Cell Reports, found that the molecule PBT2 – originally developed to treat disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases – could be repurposed to break antibiotic resistance to the commonly used antibiotic ampicillin.
Using mice as models, the researchers found that PBT2 works by amplifying the antimicrobial effect of zinc within the lungs and leads to an increased susceptibility to ampicillin. This could mean the return of readily available and cheap antibiotics to treat previously resistant strains.
According to lead researcher Professor Christopher McDevitt, from the University of Melbourne, the idea to investigate PBT2 came from prior research showing that zinc is used by the immune system against bacterial infection.
“We knew from earlier research that the immune system uses zinc as an innate antimicrobial to fight off infection,” says McDevitt. “So we developed our therapeutic approach with PBT2 to use the body’s antimicrobial zinc to break antibiotic resistance in the invading bacteria.”
They found that PBT2 upset the maintenance of optimal concentrations of metal ions within S. pneumoniae. Zinc resistance mechanisms were overwhelmed by the resulting influx of ions, disrupting numerous biochemical pathways, including those that affect bacterial cell walls.
“This rendered the drug-resistant bacteria susceptible to the antibiotic ampicillin, restoring the effectiveness of the antibiotic treatment in the infected animals,” says McDevitt.
“We knew that some ionophores, such as PBT2, had been through clinical trials and shown to be safe for use in humans,” says Griffith University’s Professor Mark von Itzstein. “We focused on bacterial pneumonia and the most commonly used antibiotics. We thought that if we could rescue frontline antibiotics and restore their use for treating common infections, this would solve a global problem.”
The rising threat of antibiotic resistance
The antibiotics we use to treat bacterial infections are becoming less and less effective. It’s predicted that by 2050, antibiotic-resistant infections will cause more deaths than cancers and cardiac disease, accounting for more than 10 million deaths per year.
The team’s discovery has the potential to provide a cost-effective and readily available treatment to life-threatening infections such as community-acquired bacterial pneumonia, which poses a serious public health risk.
“In Australia, this is of particular importance for Aboriginal and Torres Strait Islander communities who are four times more susceptible to bacterial pneumonia and 11 times more likely to succumb to infection,” says Professor Mark Walker from the University of Queensland.
While this is an important first step, McDevitt says they will now be working towards collecting the data required for a clinical trial in humans of PBT2 in combination with antibiotics.
“We also want to find other antibiotic-PBT2 combinations that have therapeutic potential for treatment of other bacterial infections,” says McDevitt. “Our work shows that this simple combination therapy is safe, but the combinations require further testing in clinical trials.”