Discovery of antibiotics and their targets in multidrug-resistant bacteria

Bakker, A.T. (2022)

Doctoral Thesis

Global healthcare is on the verge of an antibiotic availability crisis as bacteria have evolved resistance to nearly all known antibacterials. Identifying new antibiotics that operate via novel modes-of-action is therefore of high priority.
This thesis contains two drug discovery projects, originating from a antibacterial screen of a compound library. In both projects chemical hits are first structurally optimized, after which their mode-of-action is determined.
The first project entails optimizing a hit with potency against MRSA into a submicromolar active antibiotic. By using a chemical proteomics approach, the targets of this compound were elucidated, along with the targets that are most important in its antibacterial activity.

The second project concerns Gram-negative bacteria, where a hit molecule is optimized into the conformationally restricted LEI-800. The target of LEI-800 is found to be DNA gyrase, a common antibiotic target. However, it is that LEI-800 inhibits DNA gyrase differently, and more potently, than the status quo.

• Antimicrobial resistance
• Phenotypic screening
• Drug discovery
• MRSA
• Gram-negative bacteria
• Mode-of-action
• Antibiotics
• Structure-activity relationship study
• DNA gyrase
• Chemical proteomics

• All authors: Bakker, A.T.
• Supervisor: Stelt, M. van der: Martin, N.I.
• Committee: Ubbink, M.; Bogyo, M.; Hacker, S.M.; Kasteren, S.I. van; Meijer, A.H.; Sieber, S.A.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Institute of Chemistry (LIC), Faculty of Science, Leiden University
• Date: 2022-12-07
• ISBN (print): 9789464587647