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Since the discovery of penicillin in 1928, antibiotics have transformed the world of medicine. They have prevented the spread of disease, saved countless lives, and curbed the effects of infectious epidemics. Unfortunately, antibiotics have also frequently been misused, which has led to one of the largest threats to global health, food security and development: antibiotic resistance. (1)
In order to mitigate antibiotic resistance, a new strategy to increase antibiotic potency and reverse drug resistance has proven necessary. Simultaneously, the antibiotic development pipeline has run dry since the 1980s, with few new antibiotics being approved for clinical use. This means that while bacteria are growing stronger, the availability of new drugs that can fight them is failing to keep up.
The threat of strengthening bacteria
Gram-negative pathogens are a class of bacteria that represent a particular challenge to the medical community, as their outer membrane can protect them from antibiotics such as penicillin. This includes many forms of pathogenic bacteria, including E. coli, salmonella and those that cause serious illnesses such as pneumonia, tuberculosis, hospital-acquired infections and sepsis syndromes. They are found everywhere and in virtually all environments on Earth that support life.
These pathogens have been identified as the World Health Organization’s (WHO) critical priority as the surge in drug-resistance infections continue. To treat multidrug-resistant (MDR) bacterial infections (especially Gram-negative bacteria), the monotherapy of current antibiotics may no longer be adequate. As an alternative approach, combination therapy has attracted great attention.
Although both positive and negative clinical outcomes have been reported from the combination of different antibiotics for treatment of Gram-negative bacterial infections, combining antibiotics with non-antibiotic adjuvants has seen modest success in the treatment of MDR bacteria. (2)
Hence, antibiotic adjuvants with the ability to reverse antibiotic resistance phenotypes, enhance antibiotic potency and repurpose drugs as potent antibiotics are greatly needed.
Reversing resistance with science
To address this challenge, the IBM Research team, together with scientists from the Agency for Science, Technology and Research and the Singapore-MIT Alliance for Research and Technology have published new findings in Advanced Science, which unveil the effectiveness of a new polymer in the fight against resistant bacteria.
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).
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. 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 our 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.
Additionally, scientists from IBN, GIS and Singapore-MIT Alliance for Research and Technology (SMART) discovered that the polymer/rifampicin combination worked synergistically to mediate rapid and significant cytosolic stress in bacteria, and this played a final effector role in bacterial cell death after treatment with the combination.
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.
Building effective treatments for the future
IBM Research has long been a major player and leader in the fields of polymer and materials chemistry, while collaborators like IBN have deep experience in developing antimicrobial polymers and peptides. The creation of this specific polymer is built on a strong foundation and infrastructure of hypothesis-driven materials research, chemistry and biology from across the research team.
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.
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.
- (J. O’Neill, Review on Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations, Review on Antimicrobial Resistance, London, United Kingdom, 2014.)
- (P. D. Tamma, S. E. Cosgrove, L. L. Maragakis, Clin. Microbiol. Rev. 2012, 25, 450.)