Combating Antibiotic Resistance to Aminoglycoside Antibiotics through Chemical Synthesis

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The increasing number of pathogens resistant to last-line-of-defense antibiotics has led to a renewed public interest in research for novel antibiotics. Resistance to aminoglycoside antibiotics conferred by ribosomal methyltransferase enzymes is a new threat reported within the last decade. However, extensive research on the mode of action of aminoglycosides makes it feasible to defeat this resistance mechanism and combat it with chemical synthesis. Existing semi-synthetic approaches to aminoglycoside scaffolds do not allow necessary chemical modifications and prohibit the implementation of insights delivered by structural biology. This project describes a total synthesis platform for the discovery of aminoglycosides effective against methyltransferase mediated resistance. The approach focuses on the convergent assembly of antibiotics from readily available building blocks and allows deep-seated modifications to obtain chemically diverse structures. In combination with microbiological assays, a step-wise investigation and validation of the structural implications to overcome ribosomal bacterial resistance can be conducted.