Bacteria, stop!
A new class of medicines has been opened
Sergey Syrov, XX2 century
Specialists representing the Wistar Institute, the first independent non-profit biomedical research center in the USA founded at the end of the XIX century, report the discovery of a new class of medicines (Wistar Reports a New Class of Antibiotics Active Against a Wide Range of Bacteria).
The compounds act as antibiotics, directly acting on pan-resistant bacterial pathogens. At the same time, they activate the body's rapid immune response. Perhaps we see an effective means to combat the resistance of bacteria to antimicrobial drugs.
The discovery is reported in an article published in the journal Nature (Singh et al., IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance).
The World Health Organization (WHO) includes antibiotic resistance in the list of the ten largest threats to the public health of mankind. It is estimated that by 2050, antibiotic-resistant infections could claim 10 million lives annually and cause $100 trillion in damage to the global economy. The list of bacteria that are becoming resistant to treatment with all available antibiotic options is growing; we desperately need new types of antibiotics to prevent a global public health crisis.
"We have chosen a dual strategy in developing new molecules that can kill intractable infections while simultaneously enhancing the host's natural immune response," says Farokh Dotiwala, lead author of the work.
New antimicrobial drugs – double-acting immuno-antibiotics (dual-acting immuno-antibiotics, DAIAs).
Existing antibiotics target basic bacterial functions, including nucleic acid and protein synthesis, cell membrane construction, and metabolic pathways. However, bacteria acquire drug resistance, since the bacterial target against which the antibiotic is directed changes with each successful mutation for the bacterium. In essence, antibiotics act as a factor of evolution, contributing to the selection of the most resistant strains.
Dotivala and colleagues focused on a metabolic pathway that is necessary for most bacteria, but is absent in humans, making it an ideal target for the development of antibiotics. This is the pathway responsible for the synthesis of isoprenoids – molecules necessary for the survival of cells of most pathogenic bacteria. The laboratory targeted the IspH enzyme, one of the key ones in the synthesis of isoprenoids, in the hope of blocking the pathway and killing microbes in this way. Given the widespread presence of IspH in the bacterial world, it can become a tool for combating a wide range of bacteria. The substrate of IspH in humans and other primates activates cytotoxic T cells.
"We reasoned that using the immune system to simultaneously attack bacteria on two different fronts would make it difficult for them to develop resistance," explains Dotivala.
The researchers used computer simulations to test several million compounds for their ability to bind to this enzyme, selecting those with the potential to inhibit IspH function most effectively.
Previously available IspH inhibitors cannot penetrate the bacterial cell wall. Therefore, Dotivala, together with a colleague, Professor Joseph Salvino, one of the senior authors of the study, undertook to identify and synthesize new IspH inhibitor molecules that would be able to penetrate bacteria. They succeeded, prototypes of future drugs active against the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus were created. The hope that the compounds found would stimulate the immune system was also justified. At least, these are the results of tests on human cell cultures.
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