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US researchers have created a new class of antibiotics that can kill even the most chemically resistant bacteria, in what they describe as a “potential landmark.”
If marketed, hospital patients infected with ultra-strong, highly evolved “super bacteria” could take intravenous drugs – called dual-action immuno-antibiotics (DAIA) – to clear a bacterial infection.
DAIA tackles the huge, ongoing problem of Antimicrobial Resistance (AMR) – when bacteria and other microbes adapt and evolve in response to modern chemicals designed to kill them, becoming ‘super bacteria’ ‘ultra-powerful.
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, which makes us less susceptible to superbugs in the first place.
In laboratory tests, DAIA have been shown to be effective against bacteria, especially E. coli, a common source of infection that is becoming increasingly resistant to antibiotics.
DAIA even targets pan-resistant bacteria – bacteria that are resistant to all antibiotics available on the market.
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The drugs – called DAIA – have been described as a ‘potential milestone’ in the war on antimicrobial resistance (AMR)
“ We have adopted a creative two-pronged strategy to develop new molecules capable of killing hard-to-treat infections while enhancing the host’s natural immune response, ” study author Farokh Dotiwala told Wistar Institute, an independent nonprofit institution in Pennsylvania. , United States.
“ We thought that harnessing the immune system to simultaneously attack bacteria on two different fronts makes it difficult for resistance to develop.
“We believe this innovative DAIA strategy could represent a potential milestone in the global fight against antimicrobial resistance, creating a synergy between the direct killing capacity of antibiotics and the natural power of the immune system.
An entire scientific industry is now dedicated to targeting the serious problem of antimicrobial resistance (AMR) and the resulting superbugs.
The World Health Organization (WHO) estimates that these superbugs will kill 10 million people every year by 2050 – patients dying from once harmless infections – and impose a cumulative burden of $ 100 trillion on human health. Mondial economy.
Pathogens such as bacteria and fungi can evolve to become super resistant to our chemical treatments. WHO estimates superbugs will kill 10 million people each year by 2050, with patients dying from once harmless infections
The WHO has declared antimicrobial resistance as one of the top 10 global public health threats against humanity, while an expert has called the threat of antimicrobial resistance the seriousness of terrorism.
“AMR” includes antibiotic resistance (ABR) – a term specific to bacteria resistant to drugs designed to kill them (antibiotics).
To make matters worse, the list of bacteria that become resistant to treatment is growing.
Few new drugs are in the pipeline, according to the Wistar Institute, creating a “pressing need” for new classes of antibiotics to prevent public health crises.
Existing antibiotics target essential bacterial functions, including nucleic acid and protein synthesis, cell membrane construction, and metabolic pathways.
However, bacteria can acquire resistance to antibiotics through their natural ability to evolve and mutate in the fight for survival.
Specifically, bacteria mutate regardless of the specific bacterial target against which the antibiotic is directed, effectively inactivating the antibiotic in the process.
Fluorescence microscopic stain showing the effects of DAIA treatment on the viability of bacteria. The E. coli bacteria were treated with isopropanol (a bactericidal chemical compound), a carrier molecule (without destructive action) and increasing concentrations of the active drug DAIA, and stained with propidium iodide (PI, red), which stains dead cells, and SYTO 9 (green), which stains only living cells
Researchers at the Wistar Institute have focused on a metabolic pathway essential for most bacteria but absent in humans, making it an ideal target for antibiotic development.
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 pathogenic bacteria.
The lab targeted the enzyme IspH, an enzyme essential in isoprenoid biosynthesis, to block this pathway and kill microbes.
Given the large presence of IspH in the bacterial world, this approach likely targets a wide range of bacteria, the researchers say.
They then used computer modeling to screen several million commercially available compounds for their ability to bind to the enzyme.
They selected the most potent ones that inhibited IspH function as the starting points for drug discovery.
Since previously available IspH inhibitors could not penetrate the bacterial cell wall, researchers identified and synthesized new IspH inhibitor molecules capable of penetrating inside bacteria.
The team demonstrated that IspH inhibitors stimulate the immune system with more potent bacterial killing activity than the best current antibiotics.
“Immune activation represents the second line of attack in the DAIA strategy,” said study lead author Kumar Singh, also at 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” (in a glass petri dish).
The researchers said: “ In preclinical models of Gram-negative bacterial infection, the bactericide [bacteria-killing] the effects of IspH inhibitors have surpassed traditional pan antibiotics.
All of the compounds tested were found to be non-toxic to human cells.
The promising study was published in Nature.
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