Dissertation
Antibiotic Discovery: From mechanistic studies to target ID
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-target interactions and target identification.
- Author
- A.I. Kotsogianni Teftsoglou
- Date
- 20 June 2023
- Links
- Thesis in Leiden Repository
![](/binaries/content/gallery/ul2/main-images/science/proefschriften/antibioticdiscoverykotsogianni.png/antibioticdiscoverykotsogianni.png/d300xvar)
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.