The development of metal-based antibiotics

Background:

Due to the widespread rise in microbial resistance, new classes of antimicrobial agents are urgently needed. However, only very few of the compounds in clinical development represent new structural classes. Most are derivations of approved antimicrobials and all are purely organic compounds. Hence, it is likely that bacterial resistance will soon arise. 

New metal-containing antimicrobials are therefore attracting increasing attention, mainly due to their alternative modes of action, including redox activity and reactive oxygen species generation. Metal-containing compounds have long been overlooked because they were generally viewed as toxic to mammalian cells, however, it is now emerging that this is not necessarily the case.

The objectives of the project are to synthesise and explore the antimicrobial properties of a series of transfer-hydrogenation catalysts and to establish their antimicrobial activity. Harnessing the activity of synthetic transfer hydrogenation catalysts is a novel approach to disrupting the bacterial redox homeostasis. The bio-orthogonal nature of these synthetic unnatural catalysts has the potential of delaying bacterial resistance development. Biological testing will then inform the optimisation of both the activity and selectivity of the compounds.

Experimental Approach:

A series of iridium(III) complexes and related transfer-hydrogenation catalysts will be chemically synthesised and their catalytic activity in biologically-relevant media will be optimised. The antimicrobial activity of promising catalysts will be screened against a panel of reference and clinically-relevant strains of Gram-positive and Gram-negative bacteria. In addition, the toxicity of the compounds to human cells will be assessed. After screening of complexes to identify compounds with good antimicrobial activity and limited toxicity to human cells, their mode of action will be explored using bactericidal and bacteriostatic assays.

Training:

This project will provide interdisciplinary training on research skills at the interface between medicinal chemistry and microbiology. Skills training in quantitative assays and data analysis will be provided. The student will learn to design and execute suitable experiments to aid antimicrobial drug discovery, to understand kinetics and resistance mechanisms, to critically evaluate results and to develop team-working, time-management and presentation skills. In addition, the student will be encouraged to attend two major international conferences during their PhD.

Prerequisites:

The candidate must have a background in chemical synthesis and be willing to learn the microbiological aspects of the project. 

The York Biomedical Research Institute at the University of York is committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation, religion/belief, marital status, pregnancy and maternity, or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.