Cationic lipidoids: protonation-driven self-assembly and membrane- targeting antimicrobial activity James Jennings, Dunja Asceric,Nermina Malanovic, Enrico Semeraro,
Karl Lohner, Georg Pabst University of Graz, Austria
The growth of antimicrobial resistance in pathogenic bacteria is already a public health crisis, and as old treatments become ineffective ordinary infections may again become fatal.[1] Naturally occurring antimicrobial peptides (AMPs) and synthetic quaternary ammonium compounds (QACs) are among the most promising candidates for next generation treatments.[2] These amphiphilic compounds typically kill bacteria by targeting the cell membrane. However, AMPs are expensive to manufacture at scale and can be degraded by enzymes, while QACs are rarely selective against bacteria and can be toxic to human cells. Overall, the need for new antimicrobials based on soft materials is urgent, and the role of antimicrobial aggregation and self-assembly are factors that could be key in designing newcompounds. Designing new antimicrobials can be accelerated using high-throughput synthetic approaches. We recently synthesized a library of over 100 "lipidoids" with diverse chemical structures, using commercially available amine and acrylate building blocks.[3] These lipidoids particularly resemble bacterial lipids (e.g. lipid A or cardiolipin) in that they contain a number of hydrophobic tails (4 or more) and multiply-charged headgroups. Ionisation of multi-tailed lipidoids was found to impart unique molecular conformations that induce self-assembly into lamellar, bicontinuous cubic and hexagonal liquid crystals. At least 12 different compounds that can assemble into the rare double gyroid phase were identified. We have extended this study to explore how the molecular conformations and self-assembly tendencies of lipidoids impact their membrane-targeting antimicrobial behavior. By screening a library of 117 unique compounds, relationships between molecular shape and antimicrobial activity have begun to emerge. Minimum inhibitory concentration (MIC) assays show that lipidoids are effective against model Gram-negative ( E coli ) and/or Gram-positive ( B subtilis ) bacteria. Using a range of biophysical techniques we show that antimicrobial activity correlates with the ability of lipidoids to disrupt bacterial membranes. High- throughput screening shows that an interplay between headgroup size and architecture, and tail length and architecture governs the antimicrobial efficacy. In particular, lipidoids with a propensity to form non-lamellar phases under MIC assay conditions are the most effective at disrupting membranes. Furthermore, using lipidoids in hemolytic assays reveals a number of key structural features that lead to reduced activity against mammalian cell membranes and thus lowertoxicity. These findings could pave the way towards universal design rules for syntheticmembrane-disrupting antimicrobial compounds. References 1. R. Shukla, et al. Nature 608 , 390 (2022).
2. M. C. Jennings, K. P. C. Minbiole & W. M. Wuest, ACS Infect. Dis. 1 , 288 (2016). 3. J. Jennings, & G. Pabst, ChemRxiv (2022) doi:10.26434/chemrxiv-2022-q6pqt.
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