Dissecting structural and functional diversity of the lantibiotic mersacidin.
Mersacidin is a tetracyclic lantibiotic with antibacterial activity against Gram-positive pathogens. To probe the specificity of the biosynthetic pathway of mersacidin and obtain analogs with improved antibacterial activity, an efficient system for generating variants of this lantibiotic was developed. A saturation mutagenesis library of the residues of mersacidin not involved in cycle formation was constructed and used to validate this system. Mersacidin analogs were obtained in good yield in approximately 35% of the cases, producing a collection of 82 new compounds. This system was also used for the production of deletion and insertion mutants of mersacidin. The outcome of these studies suggests that this system can be extended to produce mersacidin variants with multiple changes that will allow a full investigation of the potential use of modified mersacidins as therapeutic agents.
Appleyard
Antony N
AN
Novacta Biosystems Ltd., Welwyn Garden City, Hertfordshire, UK.
Choi
Shaila
S
Read
Daniel M
DM
Lightfoot
Ann
A
Boakes
Steven
S
Hoffmann
Anja
A
Chopra
Ian
I
Bierbaum
Gabriele
G
Rudd
Brian A M
BA
Dawson
Michael J
MJ
Cortes
Jesus
J
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001430:Bacteriocins / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D005810:Multigene Family; D050505:Mutant Proteins / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D050505:Mutant Proteins; D019151:Peptide Library; D010455:Peptides; C069959:mersacidin