Carboxyl Analogue of Mutacin 1140, a Scaffold for Lead Antibacterial Discovery

Applied and Environmental Microbiology
Jerome EscanoLeif Smith

Abstract

Mutacin 1140 belongs to the epidermin group of lantibiotics. Epidermin class lantibiotics are ribosomally synthesized and posttranslationally modified antibiotics with potent activity against Gram-positive bacteria. In particular, this class is effective at targeting drug-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (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 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 that 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...Continue Reading

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Citations

Dec 23, 2017·Applied and Environmental Microbiology·Mengxin GengLeif Smith
Dec 3, 2017·Expert Opinion on Drug Discovery·Mengxin Geng, Leif Smith
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Sep 17, 2020·Natural Product Reports·Manuel Montalbán-LópezWilfred A van der Donk
Apr 4, 2021·International Journal of Molecular Sciences·Hideo YonezawaShigeru Kamiya

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