Semisynthetic Macrocyclic Lipo-lanthipeptides Display Antimicrobial Activity Against Bacterial Pathogens

Area of Science:

• Biochemistry
• Microbiology
• Medicinal Chemistry

Background:

• Antimicrobial peptides (AMPs) often rely on disulfide bonds for activity, but these bonds are unstable.
• Lanthipeptides, stabilized by methyllanthionine bonds, offer superior stability for therapeutic development.

Purpose of the Study:

• To create stable analogues of disulfide-dependent AMPs using lanthipeptide synthetase CinM.
• To enhance these analogues by adding lipid tails and evaluate their antimicrobial properties.

Main Methods:

• Utilized class-II lanthipeptide synthetase CinM to form methyllanthionine bonds in AMP analogues.
• Chemically attached lipid tails of varying lengths to the macrocyclic core peptides.
• Assessed antimicrobial activity via MIC tests, killing assays, membrane permeability, and hemolysis assays.

Main Results:

• CinM successfully installed methyllanthionine bonds in the designed analogues.
• Lipidated macrocyclic peptides exhibited bactericidal activity against Gram-positive and Gram-negative bacteria.
• Compounds disrupted bacterial membranes and lysed cells, with minimal hemolytic activity.

Conclusions:

• Developed a method to create stable, lipidated lanthipeptides with broad-spectrum antimicrobial activity.
• These findings offer a promising strategy for developing new antimicrobial therapeutics.
• The enhanced stability and targeted membrane disruption suggest a viable therapeutic approach.