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

Autor: Volynkina IA; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia., Bychkova EN; Gause Institute of New Antibiotics, B. Pirogovskaya 11, 119021 Moscow, Russia., Karakchieva AO; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia., Tikhomirov AS; Gause Institute of New Antibiotics, B. Pirogovskaya 11, 119021 Moscow, Russia., Zatonsky GV; Gause Institute of New Antibiotics, B. Pirogovskaya 11, 119021 Moscow, Russia., Solovieva SE; Gause Institute of New Antibiotics, B. Pirogovskaya 11, 119021 Moscow, Russia., Martynov MM; Gause Institute of New Antibiotics, B. Pirogovskaya 11, 119021 Moscow, Russia., Grammatikova NE; Gause Institute of New Antibiotics, B. Pirogovskaya 11, 119021 Moscow, Russia., Tereshchenkov AG; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia.; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia., Paleskava A; Department of Molecular and Radiation Biophysics, Petersburg Nuclear Physics Institute Named by B.P. Konstantiniv of NRC 'Kurchatov Institute', Mkr. Orlova Roshcha 1, 188300 Gatchina, Russia.; Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, Khlopina 11, 195251 Saint Petersburg, Russia., Konevega AL; Department of Molecular and Radiation Biophysics, Petersburg Nuclear Physics Institute Named by B.P. Konstantiniv of NRC 'Kurchatov Institute', Mkr. Orlova Roshcha 1, 188300 Gatchina, Russia.; Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, Khlopina 11, 195251 Saint Petersburg, Russia.; NBICS Center, NRC 'Kurchatov Institute', Kurchatov Square 1, 123182 Moscow, Russia., Sergiev PV; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia.; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia.; Institute of Functional Genomics, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia., Dontsova OA; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia.; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia.; Department of Functioning of Living Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Osterman IA; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia., Shchekotikhin AE; Gause Institute of New Antibiotics, B. Pirogovskaya 11, 119021 Moscow, Russia., Tevyashova AN; Gause Institute of New Antibiotics, B. Pirogovskaya 11, 119021 Moscow, Russia.; School of Science, Constructor University, Campus Ring 1, 28759 Bremen, Germany.
Jazyk: angličtina
Zdroj: Pharmaceuticals (Basel, Switzerland) [Pharmaceuticals (Basel)] 2024 Jan 31; Vol. 17 (2). Date of Electronic Publication: 2024 Jan 31.
DOI: 10.3390/ph17020187
Abstrakt: 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.
Databáze: MEDLINE
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