Structure and Activity of Class II Lanthipeptides From a Thermophilic Bacterium

Area of Science:

• Microbiology
• Biochemistry
• Structural Biology

Background:

• Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) with significant potential as antibacterial and antifungal agents.
• Class II lanthipeptides are a subclass with unique structural features and biosynthetic pathways.
• Thermoactinomyces sp. DSM 45891 is a thermophilic bacterium harboring novel RiPPs.

Purpose of the Study:

• To identify and structurally analyze the lanthipeptide produced by the tla BGC in Thermoactinomyces sp. DSM 45891.
• To investigate the modification of precursor peptides TlaA1 and TlaA2 by the lanthipeptide synthetase TlaM.
• To assess the antimicrobial activity of the modified lanthipeptide.

Main Methods:

• Coexpression of lanthipeptide synthetase TlaM and precursor peptides TlaA1/TlaA2 in Escherichia coli.
• Structural analysis of modified peptides, including dehydration and thioether ring formation.
• Assay of antimicrobial activity against bacterial pathogens, including ESKAPE strains.

Main Results:

• Two precursor peptides, TlaA1 and TlaA2, were successfully modified by TlaM.
• TlaA1 underwent 5-6 dehydrations, while TlaA2 underwent 7 dehydrations.
• Both peptides formed four thioether rings, including overlapping DL-(methyl)lanthionine rings and nonoverlapping DL-methyllanthionines, deviating from typical stereoselective formation.
• AspN-cleaved TlaM-modified TlaA1 showed antimicrobial activity against Gram-negative ESKAPE pathogens.

Conclusions:

• The study identified and characterized a novel class II lanthipeptide, named thermolanthin, from Thermoactinomyces sp.
• Thermolanthin exhibits unique structural features, including unusual thioether ring formations.
• Thermolanthin demonstrates promising antimicrobial activity against clinically relevant pathogens, suggesting its potential as a lead compound for new antibiotic development.