The use of aminoglycoside derivatives to study the mechanism of aminoglycoside 6′-N-acetyltransferase and the role of 6′-NH2 in antibacterial activity

Abstract

Aminoglycoside antibiotics act by binding to 16S rRNA. Resistance to these antibiotics occurs via drug modifications by enzymes such as aminoglycoside 6′-N-acetyltransferases (AAC(6′)s). We report here the regioselective and efficient synthesis of N-6′-acylated aminoglycosides and their use as probes to study AAC(6′)-Ii and aminoglycoside-RNA complexes. Our results emphasize the central role of N-6′ nucleophilicity for transformation by AAC(6′)-Ii and the importance of hydrogen bonding between 6′-NH 2 and 16S rRNA for antibacterial activity.

Understanding and overcoming aminoglycoside resistance caused by N-6′-acetyltransferase

“…3B) were designed to display an N-6 0 substituent containing a hydrogen bond donor for interaction with A1408, and attachment of this group via an amide bond was expected to prevent acetylation by AAC(6 0 ). 84 As expected, compounds 2a and 2b were not substrates of AAC(6 0 )-Ii. However, bacterial studies with E. coli Fig.…”

“…70,[78][79][80][81][82][83] To address this issue, compounds 2a-b ( Figure 3B) were designed to display an N-6′ substituent containing a hydrogen bond donor for interaction with A1408, and attachment of this group via an amide bond was expected to prevent acetylation by AAC(6′). 84 As expected, compounds 2a-b were not substrates of AAC(6′)-Ii. However, bacterial studies with E. coli revealed that antibacterial activity was also compromised to some extent compared to neamine.…”

A review of patents (2011–2015) towards combating resistance to and toxicity of aminoglycosides

“…[107][108][109][110][111] Nanomolar bisubstrate inhibitors where an AG is conjugated to coenzyme A (CoA) were reported. 112,113 Structure-activity relationship (SAR) studies of truncated CoA bisubstrate revealed that the pantetheinyl group is not necessary for recognition by the enzyme, but at least one phosphate group is needed. 114 Following up with amide-linked analogues, various sulfonamide-, sulfoxide-, and sulfonecontaining bisubstrate inhibitors were synthesized and found to be 40-fold less potent against AACIJ6′)-Ii when compared to their amide-linked counterparts.…”

The Future of Aminoglycosides: The End or Renaissance?

“…Auclair and co‐workers have reported amide, phosphonate, and sulfonamide‐linked aminoglycoside–CoA bisubstrates to probe AAC(6′) enzymes (Figure 19). 157–159 Additionally, 6′‐N‐acylated aminoglycosides have been applied as probes to study AAC(6′) and aminoglycoside–RNA complexes 160. These studies have provided insight into the mechanistic details of resistance enzymes like AACs and structural features of aminoglycosides that dictate how bacteria avoid the action of aminoglycosides.…”