Membrane-Disrupting Molecules as Therapeutic Agents: A Cautionary Note

Mechanistic studies have shown that aggregates of a common membrane disrupting molecule, Triton X-100, destroy the integrity of cholesterol-rich phospholipid bilayers via a catastrophic rupture process. In sharp contrast, attack on such membranes by monomers of Triton X-100 destroys their integrity through mild leakage events. This discovery of duplicity in the destruction of membrane integrity by a membrane-disrupting molecule has led to the design of derivatives of Amphotericin B that exhibit a lower tendency to aggregate and antifungal and hemolytic activities that are well-separated. An animal study with one such derivative has shown that its efficacy is similar to that of Amphotericin B but with substantially reduced toxicity. A related in vitro study of a series of derivatives of l-phenylalanine has revealed that monomers possess significant antibacterial activity, while aggregates of these same molecules exhibit hemolytic as well as antibacterial activity. Taken together, these experimental findings point to the need for paying special attention to differences in the selectivity between monomeric and aggregated forms of membrane-disrupting molecules as therapeutic agents, where monomers are expected to be the more selective species. Whether improving the selectivity of antimicrobial peptides and other antimicrobial agents is also possible by reducing their tendency to aggregate, and whether membrane-disrupting molecules can be created that exploit differences in the lipid composition between coronaviruses and mammalian cells, are two important questions that remain to be answered.