Pseudouridimycin is an inhibitor of RNA polymerase
The new antibiotic will not allow bacteria to synthesize RNA
Daria Spasskaya, N+1
An international team of scientists led by Richard Ebright from Rutgers University (New Jersey, USA) in collaboration with the Italian biotechnology company NAICONS has isolated a new antibiotic from extracts of soil microorganisms. The antibiotic, which was called pseudouridimycin, blocks the work of RNA polymerase, imitating binding to nucleotides - the natural substrates of the enzyme. The new substance has shown its effectiveness by curing mice infected with bacteria resistant to other antibiotics. The paper describing the study (Maffioli et al., Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase) is published in the journal Cell.
The most common classes of antibiotics act mainly by two mechanisms – inhibition of bacterial cell wall synthesis (like penicillin), or disruption of protein synthesis (like tetracycline). The third, perhaps less extensive group contains substances that somehow suppress the synthesis of nucleic acids – DNA and RNA. A new substance isolated by scientists from soil microorganisms belongs to this group. It binds to RNA polymerase, a protein complex that reads information from DNA and collects a matrix from ribonucleotides for subsequent protein synthesis. The antibiotic rifampicin has a similar mechanism of action.
The antibiotic was discovered by checking the activity of a library of three thousand substances obtained in the course of previous work from actinobacteria and soil fungi. The researchers were purposefully looking for a drug that would suppress the work of bacterial RNA polymerase, but not the polymerase of bacteriophage SP6 - this would mean its selectivity against bacteria. Of the entire library, two drugs had the indicated activity, but chemical analysis showed that they were the same substance. It is a dipeptide with a pseudouridine residue sewn on, and was named pseudouridimycin (abbreviated PUM).
The structure of pseudouridimycin (here and below are the drawings from the article in Cell).
Scientists have determined that the antibiotic prevents the inclusion of uridine triphosphate in the RNA chain – one of the four building blocks specific to RNA, but not DNA. X-ray structural analysis of the polymerase complex together with the PUM molecule showed that the antibiotic takes the place of a nucleotide inside the RNA polymerase and binds four very conservative amino acid residues that most bacteria have, but which are not in the active center of human RNA polymerases. This means that the spectrum of action of cougars is very wide, but at the same time it must be safe for the one who takes it.
Pseudouridimycin in the active center of RNA polymerase
Antibiotic resistance can often occur due to a single mutation that prevents the binding of an antibiotic to its target. However, in the case of cougars, the site with which it binds is too important for bacteria, and mutations inside it cause the polymerase to stop working. Of course, this does not mean that resistance to it is not developed at all – in the experiment, scientists managed to obtain resistant bacteria, but with an efficiency an order of magnitude lower than to rifampicin.
In addition, in addition to mutations inside the target, bacteria can cope with the antibiotic in other ways, for example, learn how to destroy it or throw it out of the cell, so you should not hope that the new antibiotic will become a panacea. However, so far it has worked in a test against bacteria resistant to various antibiotics and cured mice with peritonitis caused by infection with Streptococcus pyogenes.
The development of new active substances is now increasingly taking place through rational design using computer modeling. Thus, it is possible to obtain a substance with the desired properties, to which there is no natural resistance. The authors of the work, however, note that the potential of natural sources of antibiotics has not yet been exhausted, as evidenced by their finding.
Portal "Eternal youth" http://vechnayamolodost.ru 19.06.2017