AbstractsChemistry

Synthesis of aminoglycoside derivatives to combat bacterial resistance

by Feng Gao




Institution: McGill University
Department: Department of Chemistry
Degree: PhD
Year: 2007
Keywords: Chemistry - Organic
Record ID: 1809336
Full text PDF: http://digitool.library.mcgill.ca/thesisfile18273.pdf


Abstract

Aminoglycosides are broad spectrum antibiotics that act by binding to 16S rRNA of bacteria. The wide spread of aminoglycoside resistance threatens the use of these important medicines. Two general approaches can be used to address the aminoglycoside resistance problem. One is to derive the existing aminoglycoside antibiotics; the other is to develop inhibitors blocking resistance pathways.We developed a novel methodology to regio- and chemo-selectively derivatize unprotected aminoglycosides at the N-6' position, and used this method to prepare a series of amide-linked aminoglycoside-CoA bisubstrate analogs. These analogs are the first reported nanomolar inhibitors of AAC(6')-Ii, an aminoglycoside resistance-causing enzyme. They have been proved useful as mechanistic and structural probes to investigate the molecular mechanism of the catalysis by AAC(6')-Ii.Although the aminoglycoside-CoA bisubstrates are nanomolar inhibitors of AAC(6')-Ii, they are not active in cells due to their size and negative charges. A series of truncated aminoglycoside-CoA bisubstrates were next synthesized. These derivatives were used to determine key structure-activity relationships. One analog is discovered active against resistant strain in cells.Bisubstrate inhibitors containing sulfonamide, sulfone and sulfoxide linkers were synthesized and used as mechanistic probes to study mechanism of AAC(6')-Ii. Our results support the suggestion that AAC(6')-Ii may catalyze acetyltransfer without stabilization of the tetrahedral intermediate. Surprisingly, sulfide oxidation of the amide-linked bisubstrate dramatically improved inhibition of AAC(6')-Ii.Bisubstrates with linkers containing phosphoryl group (P=O) were proposed and synthesized, the biological results are under investigation. These molecules will facilitate investigations of the potential stabilization of the tetrahedral intermediate by the enzyme. Our efforts in this project also improved our chemical knowledge of phosphorus chemi Les aminoglycosides sont des antibiotiques à large spectre. Ils agissent en se fixant à l'ARN ribosomal 16S des bactéries et perturbent la synthèse protéique. L'extension rapide du phénomène de résistance aux aminoglycosides menace cependant leur efficacité. Parmi les différents mécanismes de résistance aux aminoglycosides, le plus important est la production d'enzymes inactivant l'antibiotique. Trois types d'enzymes impliquées dans ce mécanisme ont été identifiés, à savoir les aminoglycoside-N-acétyltransférases (AACs), les aminoglycoside-O-phosphoryltransférases (APHs) et les aminoglycoside-O-nucléotidyltransférases (ANTs). Deux approches peuvent être envisagées pour combattre ou contourner le phénomène de résistance. La première consiste à créer de nouveaux antibiotiques en modifiant des antibiotiques existant. L’autre implique le développement d'inhibiteurs capables de bloquer la résistance. Une nouvelle méthodologie pour la dérivatisation régio- et chimio-sélective d'aminoglycosides non protégés à la position N-6' a été développée. Cette méthode a…