Modular Metallodrug Antimicrobials

In recent years the increase in antimicrobial resistance has become a growing concern, and hence understanding the multi-facetted process of acquired resistance is an important issue in UK and global healthcare. In this project we propose to prepare Transition Metal Masked Antibiotics (TMMAs), in which our own class of silver N-heterocyclic carbene (Ag-NHC) complexes will be combined with antibiotics of proven efficacy, affording pre-existing antibacterials masked within a metal complex. These constructs may themselves possess anti-proliferative properties, and the presence of the metal may protect the antibiotic from acquired bacterial resistance mechanisms. We will therefore use our TMMAs as mechanistic probes for both 1) acquired soft metal resistance and 2) the circumvention of antibiotic resistance mechanisms by metallo-adducts of pre-existing agents. Several classes of compounds, of increasing complexity, will be investigated.
We anticipate that this approach will provide a method to understand the role of metal chelation in reactivating antibiotics against multi-drug-resistant bacteria. A student working on this project will enjoy high quality training in synthetic organic and inorganic chemistry, microbiology (including handling of pathogenic bacteria), and in the use of cutting edge spectroscopic techniques. The work is not only expected to produce high-impact publications, but has obvious potential for downstream societal and economic impact.