Polymer for super microbes
Singapore synthesized a "superbug" molecule with antibiotic-resistant bacteria
Ekaterina Rusakova, N+1
Chinese, American and Singaporean researchers have synthesized a substance with antimicrobial properties that effectively destroys ESKAPE-bacteria resistant to most antibiotics. According to scientists in Nature Communications (Chin et al., A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset), a polymer with guanidine functional groups decomposes and is non-toxic, and does not cause bacterial resistance.
The abbreviation ESKAPE combines the names of pathogens that are highly resistant to most antibiotics and cause most hospital infections worldwide. Not so long ago, a gene began to spread among bacteria that provides them with resistance to polymyxins – "stock antibiotics" that are used when others no longer work. Not surprisingly, researchers are looking for other antimicrobial substances that could effectively fight pathogens.
Including chemists and biologists synthesize antimicrobial peptides and polymers. These substances, which have a positive charge, bind to the negatively charged bacterial membrane and destroy it, which leads to cell death. Despite the effectiveness and wide spectrum of action, antimicrobial peptides are toxic, besides their production is quite expensive. Most of the described antimicrobial polymers do not decompose, and therefore can accumulate in the body and eventually become toxic. In addition, so far their activity in living organisms has not been practically studied.
Therefore, an international team of researchers led by Dr. Yi Yan Yang from the Singapore Institute of Bioengineering and Nanotechnology created a biodegradable polymer and tested its activity and possible toxicity not only in cell cultures, but also in mice. Scientists have synthesized a polycarbonate polymer with guanidine functional groups. Guanidine is a strong base; in laboratory studies it is often used for protein denaturation.
The structure of polycarbonate with guanidine functional groups (from an article in Nature Communications).
First, the researchers tested the antimicrobial activity of the polymer on bacterial cultures and found that polymers with a length of 20 links work most effectively. The toxicity of the substance was tested on rat erythrocytes and cells of embryonic human kidneys. The polymer turned out to be non-toxic to red blood cells and less toxic to human cells than the antibiotic polymyxin B, which, along with its high efficiency, is very harmful to the kidneys. The researchers also showed that polycarbonate completely decomposes within three days and the decay products are non-toxic. The authors tested the polymer activity on cultures of five ESKAPE pathogens, including Pseudomonas aeruginosa (Pseudomonas aeruginosa) and Methicillin-resistant Staphylococcus aureus (Methicillin-Resistant Staphylococcus aureus, MRSA). It turned out that the substance destroys bacteria with 99-100 percent efficiency.
Acinetobacter baumannii cells before (left) and after (right) treatment with polycarbonate with guanidine functional groups. Polymer denatures cytoplasmic proteins, killing bacteria (A*STAR, New molecule can kill five types of deadly drug-resistant superbugs)
With the help of fluorescence spectroscopy and labeled polymer, transmission and scanning electron microscopy, the researchers were able to explain the mechanism of action of the substance. To do this, they used a culture of ESKAPE-the pathogen Acinetobacter baumannii, which cause pneumonia, meningitis and a number of other infections. The polycarbonate molecules bound to the bacterial membrane and, without destroying it, penetrated into the cell. Then guanidine denatured cytoplasmic proteins and they precipitated, killing the cell.
The mechanism of action of the polymer. The molecule binds to the bacterial membrane, penetrates into the cell and denatures and precipitates cytoplasmic proteins (A*STAR).
To make sure that the bacteria do not develop resistance to polycarbonate, the researchers carried out 30 cycles of treatment of Acinetobacter baumannii cell culture with a polymer. They grew a culture and treated it with a polymer at a concentration that allowed some bacteria to survive. Then they were grown again and treated with polycarbonate again. At the same time, the researchers looked at whether the amount of substance needed for the almost complete destruction of pathogens was increasing. As a control, the scientists used the antibiotic imipenem. After 30 treatment cycles, the bacteria have not developed resistance to the polymer. For comparison, A.baumannii developed resistance to imipenem in eight cycles. In conclusion, the scientists tested the activity and toxicity of the polymer in mice. They were infected with Acinetobacter, either MRSA, a pathogenic strain of E. coli (Escherichia coli), or Klebsiella pneumoniae culture in such concentrations that, without treatment, caused 100 percent mortality within 48 hours. The animals were then injected with either a polymer or the antibiotics imipenem or vancomycin. It turned out that the polycarbonate dose required for 50 and 95 percent survival of infected animals for three out of four pathogens was lower or comparable to the amount of antibiotics.
Portal "Eternal youth" http://vechnayamolodost.ru