RESEARCH TRIANGLE PARK — An IBM Research team, together with scientists from the Agency for Science, Technology and Research and the Singapore-MIT Alliance for Research and Technology, are working to prove the effectiveness of a new polymer in the fight against resistant bacteria.

They have published new findings in Advanced Science.

Prior to the current paper, the team published work in Nature Communications describing broad-spectrum, antimicrobial guanidinium-functionalized polycarbonates — biodegradable polymers frequently studied for biomedical applications — with a unique mechanism.

A control group of pathogenic bacteria (left) compared with bacteria treated with the newly designed polymer (right). The reaction of the bacteria showed the ability of the polymer to interact with biomacromolecules in the cytosol of the pathogens, leading the researchers to explore if antibiotic resistance could be reversed by combining the polymer with antibiotic treatments.

Working with this polymer created by IBM Research, scientists from A*STAR’s Institute of Bioengineering and Nanotechnology (IBN) discovered that these polymers showed no onset of resistance after many sub-lethal treatments, due to a unique mechanism that included membrane translocation followed by precipitation of cytosolic biomacromolecules.

Additionally, multiple treatments with the polymer neither increased the effective dose, nor upregulated expression of genes associated with resistance, as evidenced by RNA sequencing performed by scientists from A*STAR’s Genome Institute of Singapore (GIS).

When combined with the new polymer, existing antibiotic drugs are able to bypass modifications in pathogenic bacteria that enable them to resist current treatments. This is achieved by the polymer attaching to cytosolic enzymes on the membrane of the pathogens.

“Given the distinctive mechanism of the guanidinium-based polycarbonate, the research team hypothesized it could provide unique opportunities to overcome antibiotic resistance phenotypes and enhance the potency of the antibiotic,” wrote James Hedrick, one of the research paper’s writers, on IBM Research Blog.

“A possible reason for reversal of antibiotic resistance phenotype and sensitization of the MDR bacteria towards antibiotic treatment is the polymer’s ability in non-specific binding to cytosolic enzymes (proteins) or genes, including those that are responsible for antibiotic resistance.”

Building on this work in the recent paper in Advanced Science, the research team put this hypothesis to the test by combining the polymer with antibiotics that are often ineffective as a result of modification by bacterial proteins.

It was discovered that in treating the MDR A. baumannii, the presence of the polymer improved the effectiveness of the existing drugs azithromycin, gentamicin, imipenem, tetracycline and colistin; reducing their effective dosages to at or below the level used for susceptible strains.

The team also used the polymer to re-purpose both the anti-tuberculosis drug rifampicin and the antirheumatic drug auranofin — which are less effective against Gram-negative bacteria — as antibiotics with strong potency against Gram-negative A. baumannii.

“These clearly demonstrate the efficaciousness of polymer–antibiotic combinations for treating highly drug-resistant bacteria,” said Hedrick.

“Going forward, we will seek to leverage the knowledge gained in this study, our prior work in automated, programmatic polymer synthesis—published last year in the Journal of the American Chemical Society— and IBM’s AI capabilities to rapidly develop novel polymeric adjuvants. Applications of these new treatments can potentially range from treating drug-resistant pathogens and cancer to new antiviral therapies,” he added.

“The global crisis of antibiotic resistance continues to grow at an alarming pace. In the absence of a new class of stronger antibiotic drugs to help curb the consequences of this resistance, applying therapeutic combination approaches such as those published in our research could hold significant potential for fighting MDR Gram-negative bacterial infections.”