The rapid spread of antimicrobial resistance poses a major threat to human health. The World Health Organization (WHO) estimates that currently more than 700,000 patients die each year due to infections with multidrug-resistant pathogens. This number is predicted to rise dramatically, with 10 million deaths annually by 2050, if no actions are taken. In order to avoid the looming prospect of a post-antibiotic age within the next few decades, a continuous development of not just new antibiotics, but more importantly, new classes of antibiotics, is imperative.
An attractive yet underexplored target for antibiotic drug development in bacteria is the fatty acid biosynthetic pathway (FasII). Fatty acids are essential components of cellular membranes. Most bacteria are unable to scavenge fatty acids from host organisms and therefore rely on de novo production.The FasII enzyme responsible for the final step in the fatty acid elongation cycle, differs significantly from the FasI pathway of mammals, plants and fungi. These enzymes, known as enoyl-acyl carrier protein reductases (ENR), have thus been recognized as an interesting target for new antibacterials with a novel mode of action.
Triclosan, one of the most common additives to consumer products worldwide, is a well-known inhibitor of the ENR enzyme FabI in a wide range of bacteria. While triclosan was found to be unsuitable as an antibiotic due to its toxicity, multiple FabI inhibitors with improved bio-availability and toxicity profiles have been reported in recent years as a potential new class of antibiotics. However, several notorious and highly pathogenic Gram-negative bacteria, including the opportunistic WHO priority I pathogen P. aeruginosa, have been shown to be resistant to FabI inhibitors. This resistance stems from the expression of FabV, an ENR isoenzyme.
The goal of this project is the development of novel FabV inhibitors, in order to re-sensitize these pathogens to antibiotics.
The responsibilities of the PhD student will be the following:
- Chemical synthesis of libraries of potential inhibitors based on current hit material
- Enzyme expression and purification
- Fine-tuning of enzymatic assays and determining in vitro activities
- Performing SAR analyses and guiding molecular design strategies to optimize the most interesting actives
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