Antibacterial agents have given us an advantage in the enduring battle against disease-causing bacteria. However, our dominance over these microbes is rapidly waning. The overuse of antibiotics has resulted in the rise of dangerous multidrug-resistant (MDR) superbugs—notoriously invincible bacteria that have sent microbiologists scrambling to search for pharmaceutical countermeasures to defeat them.
Scientists from A*STAR, Genome Institute of Singapore, IBM Almaden Research Center, Sun Yat-sen University, and the Singapore-MIT Alliance for Research and Technology have teamed up to develop a new secret weapon to disarm MDR bacteria: a novel polymer-antibiotic combo.
Polycarbonates are biodegradable polymers with a range of biomedical applications, from gene delivery to antimicrobial biomaterials. Here, the researchers developed a guanidinium-functionalized polycarbonate and showed that it reversed resistance phenotype in MDR bacteria when used in tandem with existing antibiotics. This adjuvant gave formerly sublethal doses of antibiotics the boost they needed to penetrate and destroy pathogens that previously stopped responding to treatment.
As part of the study, the researchers validated the synergistic effects of the therapeutic duo in an animal model of MDR infections, with exciting results. “From the MDR Acinetobacter baumannii mouse model, the combination treatment was able to improve the survivability of the infected mice from 20% to 80% at seven days post-infection,” said Yi Yan Yang, Covering Executive Director of A*STAR’s Institute of Bioengineering and Bioimaging (IBB).
Using RNA sequencing, Yang and colleagues found that the paired therapy enhanced antimicrobial potency by blocking the activity of genes or proteins involved in bacterial drug resistance, even after multiple doses. They also showed how combining the polymer with the anti-tuberculosis drug rifampicin caused levels of lethal reactive oxygen species to spike in bacteria, destroying them while leaving host tissues unscathed.
This new approach to treating infections paves the way for new generations of antibiotic and polymer combinations with similar synergistic effects. Yang and her team next plan on using artificial intelligence to embark on a large-scale hunt for more winning pairs. “We can also use robotic high throughput screening to screen for different combinations of polymer/antibiotic candidates,” she added.
Though the safety profiles of these novel pharmaceutical combinations still need to be assessed before their clinical adoption, Yang is optimistic that they will make an impact, adding that the team has plans to commercialize the technology. “We seek to partner with pharma companies or form a start-up, bringing this technology from the bench to the bedside.”
The A*STAR-affiliated researchers contributing to this research are from the Institute of Bioengineering and Bioimaging (IBB) and the Genome Institute of Singapore (GIS).
