Hybrid Molecules of Azithromycin with Chloramphenicol and Metronidazole: Synthesis and Study of Antibacterial Properties

Hybrid Molecules of Azithromycin with Chloramphenicol and Metronidazole: Synthesis and Study of Antibacterial Properties. Volynkina, I. A., Bychkova, E. N., Karakchieva, A. O., Tikhomirov, A. S., Zatonsky, G. V., Solovieva, S. E., Martynov, M. M., Grammatikova, N. E., Tereshchenkov, A. G., Paleskava, A., Konevega, A. L., Sergiev, P. V., Dontsova, O. A., Osterman, I. A., Shchekotikhin, A. E., & Tevyashova, A. N. Pharmaceuticals, 2024.

Paper doi abstract bibtex

The sustained rise of antimicrobial resistance (AMR) causes a strong need to develop new antibacterial agents. One of the methods for addressing the problem of antibiotic resistance is through the design of hybrid antibiotics. In this work, we proposed a synthetic route for the conjugation of an azithromycin derivative with chloramphenicol and metronidazole hemisuccinates and synthesized two series of new hybrid molecules 4a–g and 5a–g. While a conjugation did not result in tangible synergy for wild-type bacterial strains, new compounds were able to overcome AMR associated with the inducible expression of the ermC gene on a model E. coli strain resistant to macrolide antibiotics. The newly developed hybrids demonstrated a tendency to induce premature ribosome stalling, which might be crucial since they will not induce a macrolide-resistant phenotype in a number of pathogenic bacterial strains. In summary, the designed structures are considered as a promising direction for the further development of hybrid molecules that can effectively circumvent AMR mechanisms to macrolide antibiotics.

@Article{Volynkina2024,
  author         = {Volynkina, Inna A. and Bychkova, Elena N. and Karakchieva, Anastasiia O. and Tikhomirov, Alexander S. and Zatonsky, George V. and Solovieva, Svetlana E. and Martynov, Maksim M. and Grammatikova, Natalia E. and Tereshchenkov, Andrey G. and Paleskava, Alena and Konevega, Andrey L. and Sergiev, Petr V. and Dontsova, Olga A. and Osterman, Ilya A. and Shchekotikhin, Andrey E. and Tevyashova, Anna N.},
  journal        = {Pharmaceuticals},
  title          = {Hybrid Molecules of Azithromycin with Chloramphenicol and Metronidazole: Synthesis and Study of Antibacterial Properties},
  year           = {2024},
  issn           = {1424-8247},
  number         = {2},
  volume         = {17},
  abstract       = {The sustained rise of antimicrobial resistance (AMR) causes a strong need to develop new antibacterial agents. One of the methods for addressing the problem of antibiotic resistance is through the design of hybrid antibiotics. In this work, we proposed a synthetic route for the conjugation of an azithromycin derivative with chloramphenicol and metronidazole hemisuccinates and synthesized two series of new hybrid molecules 4a&ndash;g and 5a&ndash;g. While a conjugation did not result in tangible synergy for wild-type bacterial strains, new compounds were able to overcome AMR associated with the inducible expression of the ermC gene on a model E. coli strain resistant to macrolide antibiotics. The newly developed hybrids demonstrated a tendency to induce premature ribosome stalling, which might be crucial since they will not induce a macrolide-resistant phenotype in a number of pathogenic bacterial strains. In summary, the designed structures are considered as a promising direction for the further development of hybrid molecules that can effectively circumvent AMR mechanisms to macrolide antibiotics.},
  article-number = {187},
  doi            = {10.3390/ph17020187},
  url            = {https://www.mdpi.com/1424-8247/17/2/187},
}

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