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

Author:

Volynkina Inna A.1,Bychkova Elena N.2,Karakchieva Anastasiia O.1,Tikhomirov Alexander S.2,Zatonsky George V.2,Solovieva Svetlana E.2,Martynov Maksim M.2,Grammatikova Natalia E.2,Tereshchenkov Andrey G.13ORCID,Paleskava Alena45ORCID,Konevega Andrey L.456ORCID,Sergiev Petr V.137ORCID,Dontsova Olga A.138,Osterman Ilya A.1,Shchekotikhin Andrey E.2ORCID,Tevyashova Anna N.29ORCID

Affiliation:

1. Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia

2. Gause Institute of New Antibiotics, B. Pirogovskaya 11, 119021 Moscow, Russia

3. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia

4. 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

5. Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, Khlopina 11, 195251 Saint Petersburg, Russia

6. NBICS Center, NRC “Kurchatov Institute”, Kurchatov Square 1, 123182 Moscow, Russia

7. Institute of Functional Genomics, Lomonosov Moscow State University, Leninskie Gory 1, 119234 Moscow, Russia

8. Department of Functioning of Living Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia

9. School of Science, Constructor University, Campus Ring 1, 28759 Bremen, Germany

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–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.

Funder

Russian Science Foundation

Publisher

MDPI AG

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

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