Revealing Structure-Activity Relationships and Mechanisms of Action in Novel Metal-Based Antibacterial Scaffolds

This thesis explores novel metal-based chemical spaces as potential antibacterial scaffolds, elucidates their modes of action and structure-activity relationships (SAR). In Chapter 2, a class of non-toxic, Gram-positive-acting platinum-based antibacterial agents with high activity was explored. SAR studies revealed that the simplest scaffold exhibited the strongest antibacterial activity. Mode of action studies demonstrated a multifaceted mechanism of the lead compound Pt1, including visible morphological changes in bacterial DNA through DNA breaks and fragmentation, and oxidative stress through hydroxyl radical formation. In line with the multi-target mechanism, no resistance development to Pt1 was observed. Finally, we demonstrate the in vivo activity of Pt1, which significantly reduced the bacterial load in a murine S. aureus skin infection model. In Chapter 3, a one-pot, three-component combinatorial strategy for generating a library of 1440 piano-stool iridium(III) cyclopentadienyl (Cp) Schiff base complexes as potential antibacterial agents was described. Biological screening conducted using a Direct-to-Biology (D2B) approach revealed pronounced activity against the Gram-positive bacterium Staphylococcus aureus, particularly for biphenyl-substituted Cp (Cp2) complexes. A subset of the compounds exhibits potent and selective antibacterial activity with moderate mammalian cell toxicity. The selected lead compound Ir15 exhibited low-micromolar activity against a panel of Gram-positive pathogens, limited haemolysis, and moderate cytotoxicity. Initial mechanistic studies indicate that Ir15 acts via a membrane-associated mechanism and induces changes in nucleoid morphology. Chapter 4 summarises collaborative and supervised research contributions to expand the metal-based antibacterial chemical space and to mode of action studies of novel scaffolds. SuFEx click chemistry generated 192 pyridyl-triazole ligands and 576 iridium(III) complexes, revealing Cp- and ligand-dependent antibacterial activity. Furthermore, macrocyclic lactams, ruthenium(II) and iridium(III) Schiff base complexes, copper(I) photosensitisers, and rhenium(V) dioxo complexes were evaluated as potential antibacterial scaffolds. Several metal complexes showed low-micromolar activity against Gram-positive bacteria, distinct cellular effects and, in some cases, light-enhanced activity.