New antibiotic target promises to treat drug-resistant superbugs

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The World Health Organization lists antibiotic-resistant bacteria as one of the top 10 global health threats. Therefore, researchers are looking for new antibiotics to combat this resistance. Adéla Melcrová, a physiologist at the University of Groningen (Netherlands) and her colleagues have found that the relatively new antibiotic AMC-109 affects the cell membranes of bacteria by disrupting the nests. its function. This is different from most other antibiotics and could open new directions for future treatment and drug development. The results were published in the journal Nature Communications on July 7.

The AMC-109, developed at Norway’s UiT Arctic University, has shown promising results in the laboratory as well as in clinical trials against notoriously difficult-to-treat methicillin-resistant bacteria. Staphylococcus aureus (MRSA). It will soon be tested in humans (phase 3 of clinical trials). However, it is not known exactly how AMC-109 works on bacteria. «I’m surprised no one knows exactly how it works,» says Melcrová. ‘So I decided to take a look at it.’

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Many antibiotics work by punching holes in the bacterial membrane, forming a boundary between the inside and outside of the bacteria. This membrane is important for regulating what goes in and what goes out, as well as building protective cell walls around bacteria. “The drug developers, who collaborated on this study, thought that AMC-109 creates holes in the bacterial membrane, just like other antibiotics,” says Melcrová. But this is not what she found.

Disorganization leads to death

Melcrová took the membrane of Staphylococcus aureus, extracted for her by the Molecular Microbiology group of the University of Groningen. Melcrová herself works in Professor Wouter Roos’ Physiology group, where, she explains, ‘we study biology using methods from physics.’ Together with colleague Sourav Maity, Melcrová studied bacterial membranes using a High-Speed ​​Atomic Force Microscopy (HS-AFM), which quickly hits the material with a small tip, measuring thickness and hardness. of materials.

What Melcrová and Maity saw with HS-AFM were small regions of higher film thickness, suggesting some sort of structural organization. When AMC-109 is added to the membrane, these thicker regions will gather together and then dissolve. «It’s like a melting iceberg: the material is still there, but the structure is gone,» says Melcrová. ‘And apparently, disruption of these areas is enough to lead to bacterial death.’

Clumps: for once a good thing

In collaboration with the Molecular Dynamics group, Josef Melcr built a simulation model of the interaction between membranes and antibiotics, using the Martini force field. Melcrová: ‘Although experiments show us what happens, a simulation allows us to interpret what we see.’ And what simulations show is that AMC-109 forms small clusters. These clumps then penetrate the bacterial membrane.

“Any doctor will tell you that aggregation is a bad thing,” says Melcrová. ‘Some diseases are caused by protein synthesis: Alzheimer’s disease, for example. But in this case, it’s a very good thing.’ On its own, AMC-109 will also attack human cells. But by grouping together, some of the properties that are ‘hidden’ on the inside of the AMC-109 are grouped, making it safe for the human body.

Boost other antibiotics

Now, the effect of AMC-109 on bacterial membranes is clearer, opening new possibilities for future drug development. «For example,» says Melcrová, «drugs can be developed that explicitly aim to deorganize the membrane structure.» There is also evidence to suggest that disorganization disrupts bacteria’s ability to resist old antibiotics. «This is still a hypothesis,» explains Melcrová, «but it could mean that a treatment with AMC-109 could also potentially increase the effects of a ‘classic’ antibiotic.’

Four years long

Melcrová said: “I am very happy that this work is finally released. ‘It took four long years of work. We went through a lot of stress, frustration and debate, but we also enjoyed making great discoveries and solving puzzles about the effects of this unique antibiotic. The fact that one of the collaborators, Josef Melcr, is also my husband means that this project is always with me, even at home,” Melcrová said with a laugh.

Authority to solve: Melcrová A, Maity S, Melcr J, et al. Side-membrane organization is the target of an antibacterial peptidomimetic compound. General Nat. 2023;14(1):4038. two: 10.1038/s41467-023-39726-5

This article has been republished since then materials. Note: the document may have been edited for length and content. For more information, please contact the source cited.

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