Total Synthesis and In-depth Structural Modification of Klebsazolicin, An Antibiotic against Gram Negative Bacteria

Dr Liu, Han   (Principal Investigator (PI))

Professor Li Xuechen   (Co-Investigator)

Professor Chen Sheng   (Co-Investigator)

36

2021-10-01

666015

Total Synthesis and In-depth Structural Modification of Klebsazolicin, An Antibiotic against Gram Negative Bacteria

antibiotic, Gram negative, klebsazolicin, structural modification, total synthesis

Chemical Sciences

Physical Sciences (P)

17306521

General Research Fund (GRF)

2021

On-going

1 Total synthesis of klebsazolicin. We aim to develop the Fmoc-SPPS based total chemical synthetic approach of klebsazolicin. The approach will facilitate the generation of analogues bearing modifications on both the backbone and the side chain of klebsazolicin. 2 In-depth structural modification of klebsazolicin guided by the KLB-23S rRNA binding mode. Based on the known curved conformation of klebsazolicin on the binding site, we design and synthesize the cyclized analogues, aiming to improve the binding affinity via minimizing entropy penalty. To optimize the conformation of the analogues, we design a library of cyclic klebsazolin analogues, which will be generated from double mutated synthetic peptide and dibromide linkers with different length and rigidity. To maximize the π-π stacking effect in the binding model, we will modify the N-terminal cyclic amidine moiety and the heterocyclic structures in the backbone. 3 Expansion of the anti-bacterial spectrum of KLB via incorporation of uptake-improving moieties. We aim to introduce oligo-arginine tail with variable length to the C-terminus of klebsazolicin, which will help the molecule to overcome the uptake obstacle in different Gram negative strains.