Waking up to a new era in antibiotics? Bacteria can effectively hibernate during antibiotic treatment through a mechanism called persistence, and when they ‘wake up’ they can be as infectious as they were beforehand. Researchers in the PP-MAGIC project are investigating how bacteria become persisters, which could lead to the development of more effective antibiotics, as Professor Henning Jessen explains. Many of the antibiotics currently in use
PP-MAGIC project
target an active metabolism in bacteria, such as protein or DNA synthesis. However dormant bacteria, which don’t have an active metabolism and are essentially asleep, are generally not targeted by antibiotics and so can represent an ongoing threat to health. “If these bacteria ‘wake up’ again they can be as infectious as they were before,” explains Professor Henning Jessen, Chair of Bioorganic Chemistry at the University of Freiburg. Bacteria can essentially hibernate through antibiotic treatment, then wake up in more or less the same form, a mechanism called persistence. “Basically all bacteria can do this, it’s just a ramping down of metabolism,” continues Professor Jessen. “One idea about how they become persister bacteria is through the stringent response. They encounter stress – such as heat, PH changes, or limited nutrition – then go into this metabolic shutdown and become persisters. It’s actually quite easy to generate persister bacteria, because it’s a very general evasion mechanism.”
As the Principal Investigator of the ERCfunded PP-MAGIC project, Professor Jessen is now investigating a number of questions around the stringent response, including how bacteria become persisters. Molecules called magic spot nucleotides (MSNs) are known to play an important role in this respect. “This is not the only molecule regulating the stringent response, but it’s certainly very important,” says Professor Jessen. Researchers in the project have generated derivatives of these MSNs, and Professor Jessen and his colleagues are investigating whether they can be used to modulate the stringent response. “Some analogues that we generate in the lab should be inactive in a so-called ‘caged’ form. Once they are irradiated, they would be transformed into the real MSNs, a process called ‘uncaging’; then we can study how
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they affect cell growth, antibiotic resistance, and so forth,” he outlines. “There is also the possibility of not only turning them on, but also potentially reversibly switching the structures, providing the ability to turn them ‘on’ and ‘off’ repeatedly.” These MSNs are fairly well conserved in bacteria and the system is not present in humans, so in principle they represent a promising target for drug development. However, different enzymes are used to make these MSNs in different bacteria, and Professor Jessen says generating derivatives of them is a complex task. “The issue is that currently there are not many crystal structures available of these enzymes, where you could really do structure-guided design of inhibitors,” he explains. Researchers do however have the crystal structure of Staphylococcus aureus, a clinically relevant bacterium resistant to many drugs. “We already have the compounds and the enzymes, and we’re now starting the in vitro tests. The hope is that it would work on several different pathogenic bacteria, but this
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