Design, Synthesis, and Biological Evaluation of 6″-Modified Apramycin Derivatives to Overcome Aminoglycoside...

Background/Objectives: Despite their long history of clinical use, aminoglycosides remain important broad-spectrum antibiotics, exhibiting potent activity against Gram-positive, Gram-negative, and mycobacterial pathogens. However, the growing prevalence of antimicrobial resistance, along with the well-documented nephrotoxicity and ototoxicity associated with this class, underscores the urgent need for novel derivatives with enhanced pharmacological and safety profiles. Methods: In this study, we developed a synthetic approach for the synthesis of new apramycin derivatives featuring structural modifications at the 6″-position of 4-amino-4-deoxy-D-glucose residue, specifically through the introduction of aminoalkylamine and guanidinoalkylamine substituents. The synthesized compounds were evaluated for their antimicrobial activity against a broad panel of bacterial strains, including multidrug-resistant clinical isolates. Results: The obtained derivatives of apramycin demonstrated significant antibacterial activity, retaining potency against strains resistant to conventional aminoglycosides. Moreover, the new compounds exhibited the ability to circumvent aminoglycoside resistance mediated by enzymatic modification and showed reduced cytotoxicity in mammalian cell assays. Conclusions: The distinctive pharmacological properties of apramycin and its newly synthesized derivatives, particularly their resilience to common resistance mechanisms and low cytotoxicity, highlight apramycin as a valuable structural scaffold for the development of next-generation aminoglycoside antibiotics with improved efficacy and safety.