PhD defence
Antibiotic Conjugates and Natural Products as Next-Generation Strategies Against Antimicrobial Resistance
- M. Gao
- Date
- Wednesday 17 December 2025
- Time
- Location
-
Academy Building
Rapenburg 73
2311 GJ Leiden
Supervisor(s)
Summary
The work described in this thesis addresses the urgent need for innovative therapeutic approaches to combat antimicrobial resistance (AMR). The research integrates chemical synthesis, structural optimization, and biological evaluation to develop novel antibacterial agents capable of overcoming existing resistance mechanisms. In the first part of the thesis, we designed and synthesized antibiotic conjugates that link established antibiotics with functional components to improve their performance. This includes the preparation of carbapenem/metallo-β-lactamase (MBL) inhibitor conjugates and rifampicin–siderophore conjugates. Studies on the carbapenem/MBL inhibitor conjugates revealed that while direct conjugation can preserve strong enzymatic inhibition, steric constraints may limit antibacterial potency, highlighting the need for further optimization of linkers and scaffolds. In contrast, the rifampicin–siderophore conjugates demonstrated that both the linker architecture and catechol moiety are critical for activity; notably, conjugates connecting rifampicin to chlorocatechol via a short ester linker exhibited up to a 32-fold improvement in antibacterial potency against certain Gram-negative bacterial.
The second part focuses on natural products as valuable sources of bioactive scaffolds. Through the re-discovery of poriolide, a plant-derived compound with dual antibacterial and anticancer activities, we explored its structure–activity relationships and its application as a payload in antibody–drug conjugates. Collectively, this work provides new insights into the rational design of hybrid antibiotic molecules and the modern application of natural products in drug discovery, contributing to the development of next-generation therapeutic strategies against AMR.
PhD dissertations
Approximately one week after the defence, PhD dissertations by Leiden PhD students are available digitally through the Leiden Repository, that offers free access to these PhD dissertations. Please note that in some cases a dissertation may be under embargo temporarily and access to its full-text version will only be granted later.
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