Novel Antimicrobial Peptide GT-2 Achieves Broad-Spectrum Activity with Lipid-Dependent Selectivity
A newly reported antimicrobial peptide, GT-2, selectively disrupts microbial membranes while sparing mammalian cells. The peptide adopts a helical conformation in response to bacterial and fungal lipids and reduced Pseudomonas aeruginosa wound burden below the detection limit in a topical model.
Researchers have identified a broad-spectrum antimicrobial peptide, GT-2, that selectively targets bacterial and fungal membranes while sparing mammalian cells, potentially overcoming a key limitation in antimicrobial drug development.
GT-2 was discovered through proteome-informed peptide mining and deep generative sequence optimization, as reported in a study published in npj Antimicrobial Resistance. The peptide demonstrated activity against representative fungal, Gram-negative, and Gram-positive pathogens, with minimum inhibitory concentrations (MICs) ranging from 4 to 32 μg/mL. It disrupted microbial membranes, suppressed growth, and inhibited biofilm formation.
Crucially, GT-2 exhibited low toxicity to mammalian cells, causing less than 5% haemolysis at concentrations up to 500 μg/mL.
Analyses using lipid-antagonism, UV-Vis/CD spectroscopy, and all-atom molecular dynamics simulations revealed that GT-2 is largely disordered in buffer but adopts a helical, membrane-engaged conformation in the presence of phosphatidylethanolamine (PE) and phosphatidylinositol (PI)-containing bacterial and fungal membrane mimics. In contrast, membranes modeling mammalian environments, such as pure POPC or those containing cholesterol, were less permissive for peptide insertion. These findings support a lipid-dependent membrane-engagement model in which microbial lipid composition drives the conversion of the flexible peptide into its active state.
In a wound infection model, topical application of GT-2 reduced Pseudomonas aeruginosa burden below the detection limit.
The results suggest that designing flexible peptides that exploit differences in lipid environments may help address selectivity challenges in antimicrobial development.