Carboxyl Analogue of Mutacin 1140, a Scaffold for Lead Antibacterial Discovery.
Appl Environ Microbiol. 2017 May 12;:
Authors: Escano J, Ravichandran A, Salamat B, Smith L
Mutacin 1140 belongs to the epidermin group of lantibiotics. Epidermin class lantibiotics are ribosomally synthesized and post translationally modified antibiotics with potent activity against Gram-positive bacteria. In particular, this class is effective at targeting drug resistant Streptococcus pneumoniae, MRSA,Mycobacterium tuberculosis, and Clostridium difficile A C-terminal S-[(Z)-2-aminovinyl]-D-cysteine (AviCys) residue is derived from a decarboxylation of a terminal cysteine that is involved in one of the lanthionine ring formation. Studies on mutacin 1140 have revealed new insight into the structural importance of the C-terminal AviCys residue. A C-terminal carboxyl analogue of mutacin 1140 was engineered. Capping the C-terminal carboxyl group with a primary amine restores bioactivity and affords a novel opportunity to synthesize new analogues. A C-terminal fluorescein labeled mutacin 1140 analogue traps lipid II into a large lipid II lantibiotic complex, similar to what has been observed in vivo for the lantibiotic nisin. A C-terminal carboxyl analogue of mutacin 1140 competitively inhibits the activity of native mutacin 1140 and nisin. The presence of a C-terminal carboxyl group prevents the formation of the large lipid II lantibiotic complexes, but does not prevent the binding of the lantibiotic to lipid II.Importance This study addresses the importance of the C-terminal S-[(Z)-2-aminovinyl]-D-cysteine (AviCys) residue for antibacterial activity. We have learned that the post-translational modification for making the AviCys residue is presumably important for the lateral assembly mechanism of activity that traps lipid II into a large complex. The C-terminal carboxyl analogue of this class of lantibiotics is agreeable to the addition of a wide variety of substrates. The addition of fluorescein enabled in vivo visualization of the epidermin class of lantibiotics in action. These results are significant because we demonstrate that the presence of the AviCys residue is not essential for bioactivity, but more importantly the removal of the carboxyl group is essential. The ability to make a C-terminal carboxyl analogue that is modifiable will facilitate the synthesis of novel analogues of the epidermin class of lantibiotics that can be developed for new applications.
PMID: 28500042 [PubMed - as supplied by publisher]