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A second chance for a new antibiotic agent

A second chance for new antibiotic agent
Credit: Journal of Medicinal Chemistry (2024). DOI: 10.1021/acs.jmedchem.3c02382

An increasing number of bacteria have become resistant to many commonly used antibiotics. Researchers from Bochum have discovered a fresh opportunity for a potential active molecule whose predecessor was rejected. By studying its interaction with the bacterial target protein very precisely in three dimensions, they identified a previously undetected point of attack that could be targeted by this compound.

"As this point of attack only occurs in , the drug would become much more selective and its harmfulness to human cells would be reduced," explains Professor Raphael Stoll, head of the Biomolecular NMR Spectroscopy research group at the Faculty of Chemistry and Biochemistry at Ruhr University Bochum, Germany.

The researchers published their findings on April 4, 2024, in the Journal of Medicinal Chemistry.

Significant attempts 20 years ago

The study focused on the protein peptide deformylase (PDF). Involved in protein maturation processes in cells, PDF is essential for the survival of bacteria. However, it's found in both bacteria and . "Some 20 years ago, significant attempts were made to combat PDF with antibiotic agents," Stoll points out.

"Yet, the original drug candidate, actinonin, had to be discarded for several reasons. One of the problems faced was the newly discovered human PDF, which was potentially associated with side effects. Still, further research was carried out to generate modified active compounds," Hendrik Kirschner adds.

As part of his doctoral thesis, he examined PDF in detail in the current study and analyzed it from the perspective of structural biology using biomolecular nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography. These techniques enabled him to obtain a 3D structure resolved at the smallest detail.

"This is the result of many years of collaborating with our colleague Professor Eckhard Hofmann," Stoll says.

Active molecule is adapted and made more selective

"We can use these techniques to visualize surfaces and binding pockets of biomolecules and show that the binding of molecule to this protein is not static, but dynamic," Kirschner explains.

The researchers noticed that there are two different binding orientations in the protein for a modified drug molecule: In addition to the orientation that is also present in human PDF, there's another one that should, in principle, exclusively occur in bacterial PDF.

"This prompts us to modify the drug molecule so that it favors the second binding orientation," Stoll says.

As a result, the antibiotic molecule could be rendered more selective. "It could provide this candidate with a second chance," Kirschner concludes.

More information: Hendrik Kirschner et al, Toward More Selective Antibiotic Inhibitors: A Structural View of the Complexed Binding Pocket of E. coli Peptide Deformylase, Journal of Medicinal Chemistry (2024). DOI: 10.1021/acs.jmedchem.3c02382

Journal information: Journal of Medicinal Chemistry

Citation: A second chance for a new antibiotic agent (2024, May 16) retrieved 15 June 2024 from
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