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Conjugates of Aminoglycosides with Stapled Peptides as a Way to Target Antibiotic-Resistant Bacteria

Macyszyn, Julia and Burmistrz, Michal and Mieczkowski, Adam and Wojciechowska, Monika and Trylska, Joanna (2023) Conjugates of Aminoglycosides with Stapled Peptides as a Way to Target Antibiotic-Resistant Bacteria. ACS Omega, 8 (21). pp. 19047-19056. ISSN 2470-1343


Official URL: https://pubs.acs.org/doi/10.1021/acsomega.3c02071


The misuse and overuse of antibiotics led to the development of bacterial resistance to existing aminoglycoside (AMG) antibiotics and limited their use. Consequently, there is a growing need to develop effective antimicrobials against multidrugresistant bacteria. To target resistant strains, we propose to combine 2-deoxystreptamine AMGs, neomycin (NEO) and amikacin (AMK), with a membrane-active antimicrobial peptide anoplin and its hydrocarbon stapled derivative. The AMG−peptide hybrids were conjugated using the click chemistry reaction in solution to obtain a non-cleavable triazole linker and by disulfide bridge formation on the resin to obtain a linker cleavable in the bacterial cytoplasm. Homo-dimers connected via disulfide bridges between the N-terminus thiol analogues of anoplin and hydrocarbon stapled anoplin were also synthesized. These hybrid compounds show a notable increase in antibacterial and bactericidal activity, as compared to the unconjugated ones or their combinations, against Gram-positive and Gram-negative bacteria, especially for the strains resistant to AMK or NEO. The conjugates and disulfide peptide dimers exhibit low hemolytic activity on sheep red blood erythrocytes.

Item Type:Article
Subjects:Q Science > QD Chemistry
R Medicine > RM Therapeutics. Pharmacology
Divisions:Department of Biophysics
ID Code:2323
Deposited By: Dr Adam Mieczkowski
Deposited On:15 Sep 2023 07:13
Last Modified:15 Sep 2023 07:13

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