Development of metallo-inhibitors as novel antibiotic scaffolds

This is a summer student position supervised by Blake Ho from Jeannine Hess' lab. 

Introduction to the Science

Antimicrobial resistance (AMR) – the development of microorganism’s resistance to an antimicrobial drug – is a major global heath challenge. AMR is predicted to cause more than 10 million deaths annually by 2050, surpassing cancer as the leading cause of death.¹ To tackle this global issue, our laboratory is developing the next generation of antibiotics by rationally designing metal-based molecules that trigger processes to kill pathogens.

Among the several potential antibacterial mechanisms depicted in the Figure 1, the development of metallo-inhibitors binding to key bacterial proteins (e.g., bacterial type II topoisomerases) utilises traditional medicinal chemistry principles to develop new antibiotics with new mechanisms of action.

Figure 1. Overview of metal complexes (M: metal, LG: leaving group, and G: guanine) and their potential mechanisms to inhibit bacteria.  courtesy: Blake Ho and Jeannine Hess

The coordination framework of metal complexes readily renders 3D structures² (e.g. octahedral geometries), which are often difficult to achieve with purely organic compounds. We believe this property of metal complexes can be leveraged to develop unique protein inhibitors, thus paving the way to efficacious antibacterial drugs.

About the Project

Aim: Design, synthesis, and characterization of cationic and neutral metal complexes as novel inhibitors of crucial bacterial enzymes.

Tasks
1) Synthesis of organic ligands
2) Design and synthesis of cationic and neutral metal complexes 
3) Characterization of the synthesised compounds (NMR spectroscopy, mass spectrometry, and liquid chromatography–mass spectrometry (LC-MS)
4)  Determination of bacterial uptake of the prepared metal complexes by confocal microscopy

About You

Potential candidates should have a strong interest in obtaining hands-on research experience in the fields of synthetic chemistry, inorganic chemistry, and medicinal chemistry. They will expect to get exposure in a variety of chemical reactions and the methodologies to characterize target intermediates and products.

References

1.         Hess, J. (2022)

            Rational approaches towards inorganic and organometallic antibacterials.

            Biological Chemistry 403: 363-375. PubMed abstract

2.         Morrison, C.N., Prosser, K.E., Stokes, R.W., Cordes, A., Metzler-Nolte, N. and Cohen, S.M. (2019)

            Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery.

            Chemical Science 11: 1216-1225. PubMed abstract