CRITICALLY ASSESSING MEMBRANE MODEL STUDIES OF AMPS: A NETWORK OF MECHANISMS, PITFALLS, AND OPPORTUNITIES

Lipid membranes are supposed to be the main target of many types of natural or

designed molecules, such as antimicrobial peptides or their synthetic mimics,

anticancer, antiviral peptides, transfection agents, or amyloidogenic peptides. The

effects of these compounds on model membranes have been investigated and

induced membrane permeabilization or leakage is often taken as an indication for

activity. Despite decades of research and a wealth of natural and designed molecules

and high-throughput approaches, a break-through is still missing, especially regarding

much-needed alternatives to classical antibiotics. The presentation adopts the lipid

point of view, a probably underexplored option to complement a typically peptide- or

polymer-centered approach to new therapeutic molecules. The search for potent

molecules with high selectivity requires mechanistic understanding that, to date, relies

on biophysical studies of unclear relevance to the therapeutic situation or envisioned

application. This contribution will: (1) Improve knowledge on membrane

permeabilization mechanisms, pointing out the different types of independent

information in a leakage experiment. (2) Establish a network of membrane

perturbations that contribute to activity and selectivity, including leaky membrane

fusion and intrinsically unselective asymmetry stress. (3) help to design relevant

membrane model studies. Comparison between model studies and activity in complex

biological contexts requires awareness of differences and how a given experiment is

biased towards certain modes of action. We find that selectivity of polymers for certain

lipid compositions results from differences in membrane binding, but also from the

preference of the lipids for certain leakage mechanisms. Membrane fusion and

aggregation can influence membrane leakage. We cleanly distinguish asymmetry

stress and leaky fusion and examine the interrelation of other modes of membrane

perturbation. The role of the lipid composition for leaky fusion is elucidated. Avoiding

misconceptions and misinterpretation, we can make better use of the information that

has already been collected. We can improve simplified and accessible model studies

of membrane-mediated antimicrobial activity to develop future treatments against

increasingly resistant microbes.

This work was supported by the German Research Foundation (DFG 415894560).