The investigations described in this thesis lay out strategies aimed at advancing antibiotic research and development. The examples presented revolve around two main approaches: understanding drug... Show moreThe investigations described in this thesis lay out strategies aimed at advancing antibiotic research and development. The examples presented revolve around two main approaches: understanding drug-target interactions and target identification.Applications of microcalorimetry provide insights into the binding mechanism of known antibiotics and their target within the bacterial membranes. These studies provided the thermodynamic characterization of cell-wall active compounds and their cell-wall precursor or phospholipid targets.Furthermore, by repurposing a small molecule library in a microbial susceptibility screen, the discovery of two new antibiotic leads is described. A suite of target identification methods, including whole genome sequencing and MS-based chemical proteomics, led to the characterization of their mode of action. Structure activity optimization of the leads led to the discovery of a new class of DNA gyrase inhibitors, acting on a so-far unexploited site of this validated bacterial target, as well as the identification of previously unmapped pathways in S. aureus, orchestrated by series of known and unknown enzymes. Show less
