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 multidrug-resistant 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.