Researchers in the US have developed a new class of antibiotics that can kill even the most chemically resistant bacteria, in what they describe as a “potential landmark.”
When marketed, hospital patients infected with ultra-strong, highly developed ‘superbugs’ can use the intravenous drugs – called dual-acting immuno-antibiotics (DAIAs) – to clear a bacterial infection.
DAIAs are tackling 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 ultra-potent ‘superbugs’.
DAIAs work by targeting a metabolic pathway in bacteria that most of them need to survive and thrive.
At the same time, DAIAs also stimulate an immune response in humans, making us less susceptible to the superbugs in the first place.
In laboratory tests, DAIAs have been found to be effective against bacteria, including E. coli, a common source of infection that is increasingly resistant to antibiotics.
DAIAs even target pan-resistant bacteria – bacteria that are resistant to every antibiotic on the market.
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The drugs – called DAIAs – have been described as a ‘potential milestone’ in the war on antimicrobial resistance (AMR)
“We have pursued a creative, two-pronged strategy to develop new molecules that can kill difficult-to-treat infections while enhancing the host’s natural immune response,” said study author Farokh Dotiwala of the Wistar Institute, an independent nonprofit in Pennsylvania. , USA.
‘We reasoned that it is difficult for them to develop resistance if we use the immune system to attack bacteria on two different fronts at the same time.
“We believe this innovative DAIA strategy could be a potential milestone in the fight against AMR in the world, by creating a synergy between the direct killing potential of antibiotics and the natural power of the immune system.”
An entire scientific industry is now committed to tackling the serious problem of antimicrobial resistance (AMR) and the resulting superbugs.
The World Health Organization (WHO) estimates that by 2050 these superbugs will kill 10 million people each year – with patients dying from once harmless infections – and put a cumulative $ 100 trillion burden on the global economy.
Pathogens such as bacteria and fungi can evolve to become super resistant to our chemical treatments. The WHO estimates that superbugs will kill 10 million people every year by 2050, with patients dying from once harmless infections
The WHO has named AMR one of the top 10 global public health threats against humanity, while an expert has named the threat from AMR as serious as terrorism.
‘AMR’ includes antibiotic resistance (ABR) – a term specific to bacteria that are 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, leaving “ an urgent 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 develop resistance to antibiotics due to their natural ability to evolve and mutate in the struggle for survival.
Specifically, bacteria mutate the 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 (with no killing effect) and growing concentrations of the active DAIA drug, 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 focused on a metabolic pathway that is 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 disease-causing bacteria.
The lab focused on the IspH enzyme, an essential enzyme in isoprenoid biosynthesis, as a way to block this pathway and kill the microbes.
Given the wide presence of IspH in the bacterial world, this approach is likely to target a wide variety of bacteria, the researchers say.
They then used computer modeling to screen several million commercially available compounds for their ability to bind with the enzyme.
They selected the most potent that inhibited IspH function as a starting point for drug discovery.
Because previously available IspH inhibitors could not enter the bacterial cell wall, researchers identified and synthesized new IspH inhibitor molecules that could get into the bacteria.
The team showed that the IspH inhibitors stimulated the immune system with a more potent bactericidal activity than the current best-in-class antibiotics.
“Immune activation represents the second line of attack of the DAIA strategy,” said study first author Kumar Singh, also at the Wistar Institute.
They tested clinical isolates of antibiotic-resistant bacteria, including a wide variety of pathogenic gram-negative and gram-positive bacteria, ‘in vitro’ (in a glass petri dish).
Researchers said, “In preclinical models of gram-negative bacterial infection, the bactericidal [bacteria-killing] effects of the IspH inhibitors outperformed traditional pan antibiotics. ‘
All tested compounds were found not to be toxic to human cells.
The promising study has been published in Nature.