Cancer Drugs Boost Antibacterial Activity Against MRSA

Antimicrobial resistance (AMR) continues to be a significant public health threat because of the challenges in treating infections caused by resistant bacteria. As opposed to trying to develop completely new antibiotics, which presents many challenges, some researchers are exploring how to improve the function of existing antibacterial drugs.

Since antibiotic resistance genes are often activated through signaling pathways that use nucleotides or nucleosides, researchers at the University of Galway previously explored suppressing nucleotide metabolism in methicillin-resistant Staphylococcus aureus (MRSA), where they saw the bacteria become sensitive to penicillin-like drugs.^1,2 Realizing that this mechanism of action mirrored that of many cancer drugs, the researchers explored whether existing chemotherapies could work as adjuvants for antibiotics, thus boosting effectiveness.³ In a study published in mBio, the team showed that cancer drugs that disrupt specific nucleotide metabolism increased the inhibitory effect of some antibiotics in vitro.⁴

“Our findings suggest that certain drugs originally developed for cancer treatment may have the potential to be repurposed alongside antibiotics. This could offer a new strategy to re-sensitize bacteria that have become resistant to existing treatments,” said Merve Zeden, a microbiologist and study coauthor, in a press release.

The researchers trialed a panel of five cancer drugs that disrupted the production of nucleotides, as well as antifungal and antiviral medications with similar activity, for their ability to inhibit the growth of four strains of MRSA. While all five cancer drugs slowed MRSA growth at various concentrations, the antifungal and antiviral compounds did not.

Of the five cancer drugs that the team explored, four inhibited pyrimidine metabolism while one, 6-thioguanine, was a purine analog. Exploring the effects in MRSA following treatment with each of these drugs using RNA sequencing, the researchers saw differential gene expression between the pyrimidine inhibitors and the purine analog. Specifically, the pyrimidine-targeting drugs impaired cell wall formation by downregulating genes in amino acid synthesis, whereas 6-thiguanine exhibited opposite effects on gene expression, suggesting its MRSA-inhibitory actions worked through distinct mechanisms.

Seeing that pyrimidine-targeting drugs impaired MRSA’s cell wall synthesis, the researchers explored whether these compounds could boost the effects of penicillin-like drugs, which also target this process. All four of these cancer drugs synergized with two different penicillin-like drugs to reduce the growth of MRSA. In contrast, 6-thioguanine antagonized the effects of the antibacterials.

They confirmed these deficits in cell wall synthesis with fluorescent microscopy, showing that treating MRSA cells with pyrimidine-targeting cancer drugs and penicillin-like drugs reduced the incorporation of a fluorescently labeled amino acid into the cell wall and caused abnormal separation patterns, suggesting impaired growth.

Besides AMR itself, treating pathogens like MRSA is challenging because the bacteria form biofilms that further reduce the effects of antibiotics. To see whether combination treatment with cancer drugs and penicillin-like drugs could address this, the researchers treated MRSA with their pyrimidine-targeting drugs and either penicillin-like drugs or other antibiotics that work through distinct mechanisms that have been used to overcome AMR. The team showed that, while the cancer drugs interrupted MRSA biofilms individually, cotreatment with antibiotics enhanced this antibacterial effect.

James O’Gara, a microbiologist and study coauthor, said in the same press release, “We are excited by this discovery, which advances our long-term goal of finding new ways to boost the effectiveness of existing antibiotics against superbugs like MRSA. Because this approach relies on existing medications rather than developing completely new drugs, it could provide a faster route towards developing new strategies to improve patient care.”