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

The misuse and overuseof antibiotics led to the development ofbacterial resistance to existing aminoglycoside (AMG) antibioticsand limited their use. Consequently, there is a growing need to developeffective antimicrobials against multidrug-resistant bacteria. Totarget resistant strains, we propose to combine 2-deoxystreptamineAMGs, neomycin (NEO) and amikacin (AMK), with a membrane-active antimicrobialpeptide anoplin and its hydrocarbon stapled derivative. The AMG-peptidehybrids were conjugated using the click chemistry reaction in solutionto obtain a non-cleavable triazole linker and by disulfide bridgeformation on the resin to obtain a linker cleavable in the bacterialcytoplasm. Homo-dimers connected via disulfide bridges between theN-terminus thiol analogues of anoplin and hydrocarbon stapled anoplinwere also synthesized. These hybrid compounds show a notable increasein antibacterial and bactericidal activity, as compared to the unconjugatedones or their combinations, against Gram-positive and Gram-negativebacteria, especially for the strains resistant to AMK or NEO. Theconjugates and disulfide peptide dimers exhibit low hemolytic activityon sheep red blood erythrocytes.

Automated summary

The misuse and overuse of antibiotics has led to bacterial resistance, limiting the use of existing aminoglycoside antibiotics. To combat multidrug-resistant bacteria, researchers have developed a combination of neomycin and amikacin with an antimicrobial peptide called anoplin. These hybrid compounds have shown enhanced antibacterial activity against resistant strains and low hemolytic activity.