May 20, 2022

Breaking bacterial resistance to first-line antibiotics

Breaking bacterial resistance to first-line antibiotics

Researchers from The Peter Doherty Institute for Infection and Immunity, The University of Queensland (UQ), Griffith University, The University of Adelaide and St. Jude Children’s Research Hospital discovered how to repurpose a molecule called PBT2 – originally developed as a potential treatment for disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease – to break down bacterial resistance to commonly used first-line antibiotics. Their discovery could soon see the return of readily available and inexpensive antibiotics, such as penicillin and ampicillin, as effective weapons in the fight against antibiotic resistance.

A growing number of bacterial infections – such as pneumonia, tuberculosis, gonorrhea and salmonellosis – are becoming increasingly difficult to treat as the antibiotics used against them become less effective. Researchers found a way to break this bacterial drug resistance and developed a therapeutic approach to using ampicillin to treat drug-resistant bacterial pneumonia caused by Streptococcus pneumoniae in a mouse model of infection. Their results were published in the journal Cell reports.

The breakthrough was sparked when Professor Christopher McDevitt, head of laboratory at the Doherty Institute, was conducting research on bacterial resistance to antibiotics using zinc ionophores. This led to collaborations with Professor Mark Walker of UQ and Professor Mark von Itzstein of Griffith University.

“We knew that some ionophores, such as PBT2, had been through clinical trials and shown to be safe for use in humans,” Professor von Itzstein said.

Professor Walker said: ‘As a group we realized that if we could repurpose these safe molecules to break down bacterial resistance and restore the effectiveness of antibiotics, that would be a pathway to therapeutic treatment. What we needed to do was show whether PBT2 broke down bacterial resistance to antibiotic treatment without leading to even greater drug resistance.

The research by Professor McDevitt’s group has been critically important in understanding how and where treatment might be most effective. Professor McDevitt explained: “We knew from previous research that the immune system uses zinc as an innate antimicrobial to fight infection. So we developed our therapeutic approach with PBT2 to use the body’s antimicrobial zinc to break down antibiotic resistance in invading bacteria.

“This made the drug-resistant bacteria susceptible to the antibiotic ampicillin, restoring the effectiveness of antibiotic treatment in infected animals.”

According to Professor von Itzstein, the discovery has the potential to provide a cost-effective and readily available treatment for life-threatening infections such as community-acquired bacterial pneumonia, which pose a serious risk to public health. Professor McDevitt said researchers are currently working to collect the data needed for a clinical trial of PBT2 in combination with antibiotics.

“We also want to find other antibiotic-PBT2 combinations that have therapeutic potential for treating other bacterial infections,” he said.

“Our work shows that this simple combination therapy is safe, but the combinations need testing in clinical trials. What we need now is to move forward with further testing and pharmacology.

Image credit: © Komlen

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