G1405 Ribosomal Methyltransferase-Driven Antibacterial Resistance Affects the 4,5-Disubstituted-2-deoxystreptamine Class of Aminoglycoside Antibiotics

The 4,5-disubstituted-2-deoxystreptamine (DOS) aminoglycosides (AGAs) and the 4-monosubstituted DOS AGA apramycin have long been known not to be affected by N7 methylation of the 16S rRNA base G1405, a critical mechanism of aminoglycoside resistance caused by ribosomal methyltransferases (RMTases). This puts the 4,5-AGAs and apramycin in a class apart from the 4,6-AGAs, whose action is blocked by RMTase-mediated G1405 N7 methylation and has rendered them attractive candidates for modification in drug-discovery campaigns. Contrary to this common perception, we reveal that multiple modifications of the 4,5-AGAs result in compounds whose minimum inhibitory concentrations are affected by G1405 N7 ribosomal methyltransferases. We argue that the combination of destabilization of the drug-ribosome complex caused by drug modification and G1405 N7 methylation, each of which alone may be insufficient to negatively impact activity, can result in reduced antibacterial activity. In contrast, AGA modifications that enhance affinity for the drug binding pocket will afford compounds that are not susceptible to G1405 RMTase activity, as is found for propylamycin and the apralogs. Future antibiotic discovery campaigns based on 4,5-AGAs and apramycin should take these findings into account.