Antibiotic Resistance Breakers: Design and Synthesis of OXA-48 Inhibitors

Abstract

Antibiotic resistance is threatening the achievements of modern medicine and will evidentially lead to a situation, in which we stand helpless against common bacterial infections. The largest and most widely used group of antibiotics are the β-lactams. One of the major resistance determinants against β-lactam antibiotics is the expression of hydrolytic enzymes, called β-lactamases (BLs). The main concern of BLs is that they are threatening the most important group of β-lactam antibiotics, carbapenems.

A plausible solution to overcome the resistance introduced by BLs is the combination of antibiotics and inhibitors. In this thesis efforts are made towards deactivation of a BL, more specifically a carbapenemase, called OXA-48 by the synthesis of inhibitors. The synthetic strategies and computational foundations for a new fragment library are presented within, using four main reactions: Suzuki-Miyaura cross coupling, reductive amination, tetrazole formation and ester hydrolysis.

New inhibitors were synthesized and tested towards the activity of OXA-48, the most promising showing IC50 value of 3.3 µM.