Authors: Qiaomingxuan Liu | Shiwei Zhang | Margaret Pywell | Alysha G. Elliott | Holly Floyd | Johannes Zuegg | Jessica Rose Tait | John F. Quinn | Michael R. Whittaker | Muhammad Bilal Hassan Mahboob | Cornelia B. Landersdorfer
Source: bioRxiv (Cold Spring Harbor Laboratory) (article, 2026-04-02)
Field: Chemistry — Organic Chemistry

Harnessing Diacylglycerol-Terminated Cationic Oligomers for Next-Generation Antibacterial Therapeutics Abstract Cationic polymers, which mimic the structure of antimicrobial peptides (AMPs), are increasingly recognized as promising antimicrobial materials. Here, we report the synthesis and evaluation of a new class of cationic lipid-terminated oligomers (CLOs), comprised of 2C 18 -hydrophobic lipid tails, and short oligomeric cationic chains synthesised via Cu(0)-mediated reversible-deactivation radical polymerization (RDRP). Two 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers with degrees of polymerization (DP) of 20 or 50 were synthesized using the lipid functional initiator (R)-3-((2-bromo-2-methylpropanoyl) oxy)propane-1,2-diyl dioctadecanoate (2C 18 -Br). Post-polymerization modification of the pendant oxazolone moieties was carried out using reactive amines, including N -Boc-ethylenediamine (BEDA) and N,N -dimethylethylenediamine (DMEN). Subsequent deprotection of the BEDA groups and quaternization of DMEN groups enabled the synthesis of six functional CLOs exhibiting distinct cationic functionalities. Antimicrobial assays against a panel of WHO bacterial and fungal priority pathogens (methicillin-resistant Staphylococcus aureus [MRSA], Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Candida albicans, and Cryptococcus neoformans ) revealed that these CLOs exhibited potent and selective structure-dependent antibacterial activity, particularly against MRSA, with minimum inhibitory concentrations (MICs) in the clinically relevant range, below 4 µg mL -1 , comparable to antibiotics vancomycin and colistin. Among these, BEDA-functionalized CLOs demonstrated the strongest antimicrobial profile, which was significantly increased by increasing DP, as evidenced by a reduction in MIC values from 64 µg mL -1 (for DP20) to ≤ 4 µg mL -1 (for DP50) against A. baumannii . Biocompatibility assays against red blood cells and HEK293 cells indicated negligible toxicity, with haemolytic (HC 50 ) and cytotoxic (CC 50 ) values exceeding 512 µg mL-1 across all CLOs. All CLOs displayed minimal activity against C. albicans (MIC ≥ 512 µg mL -1 ). In contrast, activity against C. neoformans was influenced by both cationic functionality and DP, with DMEN-based CLOs exhibited superior antifungal activity at higher DP relative to their BEDA-based counterparts. Most CLOs displayed high selectivity (SI) toward MRSA (SI &gt;128), while 2C 18 -O(BEDA) 50 exhibited the broadest spectrum, showing potent antimicrobial activity and high selectivity against E. coli (MIC ≤ 4 µg mL -1 , SI ≥ 128), A. baumannii (MIC ≤ 4 µg mL -1 , SI ≥ 128), and MRSA (MIC ≤ 4 µg mL -1 , SI ≥ 128), along with moderate activity against P. aeruginosa (MIC = 32 µg mL -1 , SI &gt; 16). Taken together, these findings elucidate the combined influence of end-group lipidation, cationic functionality, and polymer length in modulating antimicrobial activity, thereby establishing 2C 18 -terminated CLOs as a rationally tunable and biocompatible platform for antimicrobial material development. Cationic polymerization ; Antimicrobial ; Staphylococcus aureus ; Cytotoxicity ; Escherichia coli ; Antibacterial activity ; Cryptococcus neoformans Antimicrobial agents and applications ; Advanced Polymer Synthesis and Characterization ; Polydiacetylene-based materials and applications