Antibiotic resistance is a multifactorial problem that demands multifaceted strategies to address. Here we present a drug-target network analysis of the clinically most prominent mechanism of resistance to aminoglycoside antibiotics, i.e. enzyme mediated modification of the antibiotics. This drug-target network displays prominent resistance preferences for 4,6-disubstituted aminoglycosides such as tobramycin and gentamicin, reflective of their extensive clinical usage. Further analysis also highlights aminoglycosides that remain more resilient to modifications by various bacterial resistance enzymes. This aminoglycoside resistance drug-target network conveys a compelling case for prioritization of next-generation aminoglycosides development exploiting 4,5-disubstituted and non-deoxystreptamine aminoglycoside scaffolds to surmount rising drug-resistance, in conjunction with advancing inhibitor/adjuvant leads effective against multiple aminoglycoside modifying enzyme.