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

## TL;DR

This paper shows that certain modified versions of 4,5-AGA antibiotics can lose effectiveness due to ribosomal methylation, which was previously thought to not affect them.

## Contribution

The study reveals that modifications to 4,5-AGAs can make them susceptible to G1405 N7 methylation, challenging prior assumptions about their resistance mechanisms.

## Key findings

- Modifications to 4,5-AGAs can lead to reduced antibacterial activity when combined with G1405 N7 methylation.
- Enhancing drug binding affinity can protect antibiotics from RMTase effects, as seen with propylamycin and apralogs.
- Antibiotic design should consider the interplay between drug modifications and ribosomal methylation.

## Abstract

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.