U.S. researchers have created a new class of antibiotics that can kill even the most chemical-resistant bacteria, in what they describe as a “potential benchmark.”
If marketed, hospital patients infected with very strong and highly evolved “superbugs” could take the drugs intravenously (called double-acting immunotibiotics (DAIAs)) to eliminate a bacterial infection.
DAIAs face the huge ongoing problem of antimicrobial resistance (RAM): when bacteria and other microbes adapt and evolve in response to modern chemicals designed to kill them, becoming ultra-bugs. strong.
DAIAs work by targeting a metabolic pathway in bacteria that most need to survive and thrive.
At the same time, DAIAs also stimulate an immune response in humans, making us less susceptible to superferences.
In laboratory tests, DAIAs were shown to be effective against bacteria, including E. coli, a common source of infection that is becoming increasingly resistant to antibiotics.
DAIAs even target pan-resistant bacteria: antibiotic-resistant bacteria on the market.
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Drugs, called DAIA, have been described as a “potential benchmark” in the war on antimicrobial resistance (AMR).
“We have adopted a two-pronged creative strategy to develop new molecules that can kill difficult-to-treat infections and enhance the host’s immune response,” study author Farokh Dotiwala told the Wistar Institute, an independent institution nonprofit from Pennsylvania. , WE.
“We reasoned that harnessing the immune system to simultaneously attack bacteria on two different fronts makes it difficult for them to develop resistance.
“We believe that this innovative DAIA strategy can represent a potential milestone in the global fight against AMR, creating a synergy between the direct killing ability of antibiotics and the natural power of the immune system.”
Now an entire science industry is engaged in attacking the serious problem of antimicrobial resistance (RAM) and the resulting superbugs.
The World Health Organization (WHO) estimates that these superheroes will kill 10 million people each year by 2050 (with patients dying from harmless infections) and impose a cumulative burden of $ 100 trillion on the world economy. .
Pathogens such as bacteria and fungi can evolve to be super resistant to our chemical treatments. The WHO estimates that superheroes will kill 10 million people each year by 2050, and patients die from harmless infections
The WHO has declared AMR as one of the world’s top ten threats to humanity for public health, while one expert has described the threat of AMR as serious as terrorism.
“RAM” includes antibiotic resistance (ABR), a specific term for drug-resistant bacteria designed to kill them (antibiotics).
To make matters worse, the list of bacteria that become resistant to treatment grows.
According to the Wistar Institute, there are few new drugs in preparation, which creates “an urgent need” for new classes of antibiotics to prevent public health crises.
Existing antibiotics target essential bacterial functions, including the synthesis of nucleic acids and proteins, the construction of the cell membrane, and metabolic pathways.
However, bacteria can acquire antibiotic resistance through their natural ability to evolve and mutate in the struggle for survival.
Specifically, bacteria mutate any specific bacterial target against which the antibiotic is directed, effectively inactivating the antibiotic in the process.
Fluorescence microscopy staining showing the effects of DAIA treatment on bacterial viability. E.coli bacteria were treated with isopropanol (a bactericidal chemical compound), a carrier molecule (without lethal action) and increasing concentrations of the active drug DAIA, and stained with propidium iodide (PI, red), which stains cell Dead cells, and SYTO 9 (green), which only stains living cells
Researchers at the Wistar Institute focused on a metabolic pathway that is essential for most bacteria but does not exist in humans, making it an ideal target for the development of antibiotics.
This pathway, called methyl-D-erythritol phosphate (MEP) or non-mevalonate pathway, is responsible for the biosynthesis of isoprenoids, molecules necessary for cell survival in most disease-causing bacteria.
The lab targeted the enzyme IspH, an enzyme essential in isoprenoid biosynthesis, as a way to block this pathway and kill microbes.
Given the widespread presence of IspH in the bacterial world, this approach is likely to target a wide range of bacteria, according to the researchers.
They then used computer modeling to examine several million commercially available compounds for their ability to bind to the enzyme.
They selected the most potent ones that inhibited IspH function as starting points for drug discovery.
Since previously available IspH inhibitors could not penetrate the bacterial cell wall, the researchers identified and synthesized new IspH inhibitor molecules that were able to enter the bacteria.
The team showed that IspH inhibitors stimulated the immune system with more potent bacterial activity than most current antibiotics.
“Immune activation represents the second line of attack of the DAIA strategy,” Kumar Singh, lead author of the study, also told the Wistar Institute.
They tested clinical isolates of antibiotic-resistant bacteria, including a wide range of pathogenic gram-negative and gram-positive bacteria, ‘in vitro’ (on a Petri dish).
The researchers said: “In preclinical models of gram-negative bacterial infection, the bactericide [bacteria-killing] the effects of IspH inhibitors outweighed traditional antibiotics.
Not all tested compounds were shown to be toxic to human cells.
The promising study has been published in Nature.