Dual targeting of the class V lanthipeptide antibiotic cacaoidin

• DOI: 10.1016/j.isci.2023.106394
• Publication Date: 2023-03-11T07:10:10Z
• Authors: Julia P. Deisinger; Melina Arts; Ioli Kotsogianni; Jan-Samuel Puls; Fabian Grein; Francisco Javier ...; Nathaniel I. Martin; Anna Müller; Olga Genilloud; Tanja Schneider
• Keywords: Lipid II; Lanthionine; Residue (chemistry); Natural product; Mode of Action

Antibiotic resistance is reaching alarming levels, demanding for the discovery and development of antibiotics with novel chemistry mechanisms action. The recently discovered antibiotic cacaoidin combines characteristic lanthionine residue lanthipeptides linaridin-specific N-terminal dimethylation in an unprecedented N-dimethyl ring, being therefore designated as first class V lanthipeptide (lanthidin). Further notable features include high D-amino acid content a unique disaccharide substitution attached to tyrosine residue. Cacaoidin shows antimicrobial activity against gram-positive pathogens was shown interfere peptidoglycan biosynthesis. Initial investigations indicated interaction precursor lipid IIPGN described several lanthipeptides. Using combination biochemical molecular studies we provide evidence that natural product demonstrated exhibit dual mode action combining binding direct inhibition cell wall transglycosylases.