Scientists have found a more effective way to treat bacterial infections using derivatives of triphenylphosphonium, an organic compound that is used to deliver therapeutic drugs inside infected cells. They proved for the first time that triphenylphosphonium derivatives can act as antibiotics capable of killing a pathogen that damages the cell. The study was conducted by employees of the Moscow Institute of Physics and Technology (MIPT) together with colleagues from Moscow State University named after M. V. Lomonosov (Moscow State University).Triphenylphosphonium derivatives are actively used as vectors of antibiotic delivery to cells and help them survive and recover from infection, but they have always been considered quite toxic and this seriously limited their use. In the study, scientists came to the conclusion that this toxicity is the suppression of metabolism and a change in adhesion. At the same time, single cells suffer more than in the composition of tissues. This is an unexpected and unpredictable result. According to experts, these compounds may become especially popular in the future in the treatment of dangerous bacterial diseases, such as tuberculosis and staphylococcal infections.
The search for antibiotics that act selectively, that is, strike bacteria without affecting the nuclear cells of living organisms, remains a difficult task. In addition, the treatment of infections complicates the development of bacterial resistance to antibiotics. Therefore, today scientists are actively working on the creation of alternative antibacterial agents and effective ways of delivering antibiotics to the cell, leveling the risks.
Experts consider the development of drugs based on protonophores to be promising (they transfer protons through the membrane, reducing its potential difference), capable of selectively penetrating into the bacterial cell and destroying bacteria without touching healthy eukaryotic cells. One of these compounds is triphenylphosphonium, whose derivatives are already used as vectors for delivering antibiotics to cells.
Scientists at MIPT and the Belozersky Research Institute of Physico-Chemical Biology of Moscow State University have discovered that triphenylphosphonium derivatives, being protonophores, not only help cells survive and recover from infection, but also act as antibiotics that can kill a pathogen that damages the cell. During the experiments, it was proved that the compounds have selective toxicity: they do not act on all cells, as usual, but only on certain tissues.
“Triphenylphosphonium derivatives have a negative effect on bacterial cells and a positive effect on the general cells of the body. This opens up a wide range for their use, for example, getting into the liver, they will not harm the common cells of the body, but they will kill bacteria and other individual cells,” said Pavel Nazarov, an employee of the A.N. Belozersky Research Institute of Physico—Chemical Biology of Moscow State University, associate professor of the Center for Educational Programs of the Phystech School of Biological and Medical physics of MIPT.
Triphenylphosphonium derivatives contribute to slowing down the processes in the bacterial cell: it loses the ability to divide, synthesize proteins and spend all the remaining energy on pumping out the antioxidant.
“Triphenylphosphonium derivatives reduce the membrane potential of mitochondria and bacteria, but this mechanism remains unknown until the end. The most likely scenario is the transfer of hydrogen ions through membranes due to free fatty acids, which, apparently, are universal for mitochondria, prokaryotes and eukaryotes. Toxicity plays an important role in the development of antibacterial agents, so understanding the causes of its occurrence can seriously facilitate their development. In our work, we have shown that the observed toxicity is the result of suppression of metabolism,” said Ilya Manukhov, head of the Laboratory of Molecular Genetics at MIPT.
The results of the study, conducted with the support of the Ministry of Education and Science of Russia, the Russian Science Foundation, and the Russian Foundation for Basic Research, are published in a highly rated international journal.
