Our fight against antibiotic-resistant bacterial strains is still uneven. Over the past three decades, only one new antibiotic has been introduced with a different effect than the previous one. Perhaps the situation will change the discovery of American scientists who have found the connection "awakening" bacteria from their forms insensitive to treatment.
At the beginning of using antibiotics, it seemed that defeating almost any disease caused by bacteria is within reach. The widespread use of antibiotics (in the food industry or the administration of antibacterial drugs even when they were not needed) has meant that today we face the problem of bacterial resistance to available antibiotics.
Microorganisms have developed many defense mechanisms that make the treatment administered ineffective. Some bacteria fight antibiotics with special enzymes that break down their drugs (eg β-lactamases). Others modify the places where antibiotics were involved. An example of the latter may be staphylococci resistant to methicillin treatment (MRSA strains).methicyllin-resistant Staphylococcus aureus), changing the structure of proteins to which β-lactams or enterococci VRE bound, modifying cell wall fragments to which glycopeptides joined. Some bacteria can also actively get rid of antibiotics from the cell or change the permeability of membranes so that drugs can not enter it.
Another way is to pass the bacteria into a "sleep" state. These bacterial cells are metabolically inactive, and the majority of antibiotics known to us only work on microorganisms that grow and multiply. When the cell does not metabolize, the drug can not work. The passage of bacteria into the "sleep" state is the cause of recurrent infections, including those dangerous to life. The latest mechanism is to fight a new drug discovered by scientists at Brown University. The importance of this research may be demonstrated by the fact that the results of the experiment were published in the most prestigious scientific journal, i.e.Nature”.
Of 82 thousand one
Researchers studied 82 thousand synthetic, small chemical molecules in terms of the effectiveness of treatment of MRSA infections in the nematodeCaenorhabolitis elegans (known animal model). It turned out that only 185 compounds protected the nematode from death due to infection. Two compounds with the most promising properties were selected from this group: CD437 and CD1530. Both molecules belong to retinoids, derivatives of vitamin A. Same retinoids are well-known in medicine and used in many diseases, including skin. Both compounds, CD437 and CD1530, caused distortions in the cell wall structures of Gram (+) bacteria. Their cell wall is made of murein, and stopping the production of murein means cell death. We know antibiotics that can block the production of murein, but only for cells that are not "dormant".
After selecting the two most promising compounds, scientists using molecular modeling methods investigated the interaction of these substances with the bacterial cell wall and membrane. Next, it was investigated whether these compounds act selectively on bacterial cells or whether they may, however, affect host cells (ie humans). It turned out that both CD437 and CD1530 were able not only to kill bacteria, but also human liver cancer cells under conditionsin vitrowithout destroying normal cells (which is bad news when we consider both compounds as antibiotics, good - when we think of them as new potential cancer drugs). Researchers chemically modified the CD437 compound and it turned out that after this change it only acted on bacterial cells.
Such a CD437 analogue was then administered to mice. A sufficiently high concentration in the blood was reached to kill the bacteria without causing damage to the internal organs (they were worried about the liver and kidneys).It turned out that the new drug substance proved to be the most effective when it was administered with gentamicin, a known antibiotic, which, however, does not show activity against metabolic dormant bacteria. The probable mechanism consisted in "awakening" by a new drug of the bacterial cell from "lethargy", which resulted in its greater sensitivity to the standard antibiotic.
It remains to be hoped that the discovery of American scientists will soon be on the market.
W. Kim, et al.,A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 556 (2018) 103-107