PhD defence

Natural Product Antibiotics: Synthesis and Next Generation Analogues

• V. Lysenko

Date

Thursday 21 May 2026

Time

13:00 - 14:00 hour

Address

Academy Building
Rapenburg 73
2311 GJ Leiden

Supervisor(s)

• Prof.dr. N.I. Martin

Summary

This thesis addresses the urgent challenge of antimicrobial resistance through the discovery and modification of natural product antibiotics. It combines multiple methods, including structure elucidation, total synthesis, structural optimization, and biological evaluation, to overcome resistance mechanisms and enhance the effectiveness of antibiotics. The first chapter reporting original research (Chapter 2) details the discovery, isolation, structural elucidation, and total synthesis of a new class of lipopeptides called paenilipoheptins. This work enabled the full structure determination of the paenilipoheptin core and a comprehensive biological evaluation of paenilipoheptin A, which demonstrates selective activity against Gram-positive pathogens. Chapter 3 describes the total synthesis and revised structural assignment of the recently discovered antitubercular natural product evybactin. The robust synthetic approach developed provides access to multi-hundred-milligram quantities of evybactin, which had previously been difficult to obtain from the natural producing microorganism. Chapter 4 leverages this optimized synthetic route for structure-activity relationship studies on evybactin, identifying the N-terminus as the most promising site for future modification and conjugation strategies. The final scientific chapter (Chapter 5) explores a “Trojan horse” approach to enhance rifampicin’s effectiveness against Gram-negative pathogens, demonstrating that both siderophore and linker design are crucial for the compound’s potency, with the most effective rifampicin-siderophore conjugate achieving up to a 32-fold increase in activity compared to the unmodified rifampicin. Overall, this thesis advances strategies for developing next-generation therapeutics against antimicrobial resistance.

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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