Metal-based Antimicrobials: Tackling Resistance with Catalytic Redox Stressors

Background:

New antibiotics are urgently needed to combat the widespread rise in resistance. However, only very few of the drug candidates in clinical development represent new structural classes. Most are derivations of existing antimicrobials and entirely organic molecules. Hence, it is likely that bacterial resistance will soon arise.

Due to their fundamentally-different modes of action, metal-containing antimicrobials represent promising alternatives that offer bio-orthogonal redox behaviour and catalytic properties. Metal-containing compounds have long been overlooked since they were assumed to be toxic to mammalian cells, however, it is now emerging that this is often not the case.

Objectives:

Many metal-containing compounds exhibit potent antimicrobial properties and are nevertheless well-tolerated by mammalian cells, including in mice. Numerous organometallic compounds that show this selectivity for prokaryotes over eukaryotes function as transfer-hydrogenation catalysts (THCs) and hence have the ability to disrupt the NADH/NAD+ ratio within bacterial cells, thereby inducing metabolic stress.

Our objectives are to synthesise a series of THCs and explore their antimicrobial properties. In addition, the toxicity of the catalysts to human cells will be assessed to gauge potential side effects. Biological testing will inform the further optimisation of the compounds.

Novelty:

The project benefits from a new type of THC that we have developed specifically to achieve drastically-enhanced reaction rates in aqueous buffer. We intend to harness this catalytic activity to disrupt bacterial redox homeostasis. We believe that the bio-orthogonal nature of our synthetic unnatural catalysts has the potential of delaying resistance development.

Timeliness:

Metal-based antimicrobials represent a timely opportunity to tap into, since the improved understanding of the biological activities of organometallic drugs has led to greater recognition of their medicinal potential both in academia and industry.

Experimental Approach:

A series of water-compatible THCs will be synthesised in the first supervisor’s laboratory and their catalytic activity in biological media will be optimised. The antimicrobial activity of promising THCs will be screened against a panel of reference and clinically-relevant strains of Gram-positive and Gram-negative bacteria (CO-ADD and second supervisor), and strains isolated from patients with common, serious infections, such as E. coli or S. aureus bloodstream infection, at the Medical School (third supervisor). In addition, the toxicity of the compounds to human cells will be assessed. After screening of complexes to identify THCs with both promising antimicrobial activity and limited toxicity to human cells, modes of action will be explored using bactericidal and bacteriostatic tests alongside compound localisation assays.

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